Penyakit Prion

Penyakit prion
Jurnal 1
Hum Mol Genet. 2012 April 15; 21(8): 18971906.
Publi!e" online 2011 #e$ember %0. "oi: 10.109%&!m'&""r607
PM()#: PM(%%1%791
Genome-wide association study in
multiple human prion diseases suggests
genetic risk factors additional to PRNP
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Abstract
Prion "ie+e +re ?+t+l neuro"e'ener+ti@e "ie+e o? !um+n +n" +nim+l $+ue" b2 t!e
mi?ol"in' +n" +''re'+tion o? prion protein (PrP). M+mm+li+n prion "ie+e +re un"er
tron' 'eneti$ $ontrol but ?e4 ri0 ?+$tor +re 0no4n +i"e ?rom t!e PrP 'ene lo$u
(PRNP). 5o 'enome74i"e +o$i+tion tu"2 (G;A*) !+ been "one +i"e ?rom + m+ll
+mple o? @+ri+nt (reut<?el"t-+0ob "ie+e ((-#). ;e $on"u$te" G;A* o? por+"i$
(-# ((-#), @+ri+nt (-# (@(-#), i+tro'eni$ (-#, in!erite" prion "ie+e, 0uru +n"
reit+n$e to 0uru "epite +tten"+n$e +t mortu+r2 ?e+t. A?ter Du+lit2 $ontrol, 4e
+n+l2e" 2000 +mple +n" 6015 $ontrol in"i@i"u+l (pro@i"e" b2 t!e ;ell$ome 1rut
(+e (ontrol (onortium +n" 6E8A7'en) ?or >910%27511862 *5P in t!e :urope+n
tu"2. Ao$i+tion tu"ie 4ere "one in e+$! 'eo'r+p!i$+l +n" +etiolo'i$+l 'roup
?ollo4e" b2 e@er+l $ombine" +n+l2e. 1!e PRNP lo$u 4+ !i'!l2 +o$i+te" 4it! ri0
in +ll 'eo'r+p!i$+l +n" +etiolo'i$+l 'roup. 1!i +o$i+tion 4+ "ri@en b2 t!e 0no4n
$o"in' @+ri+tion +t r1799990 (PRNP $o"on 129). 5o non7PRNP lo$i +$!ie@e" 'enome7
4i"e i'ni?i$+n$e in t!e met+7+n+l2i o? +ll !um+n prion "ie+e. *5P +t t!e ZBTB38
RASA2 lo$u 4ere +o$i+te" 4it! (-# in t!e .6 (r295%01, P F %.1% G 10
H8
; E8, 0.70)
but t!ee *5P !o4e" no repli$+tion e@i"en$e o? +o$i+tion in Germ+n (-# or in
P+pu+ 5e4 Guine+7b+e" tet. A *5P in t!e CHN2 'ene 4+ +o$i+te" 4it! @(-# IP F
1.5 G 10
H7
; o"" r+tio (E8), 2.%6J, but not in .6 (-# (P F 0.0>9; E8, 1.2>), in Germ+n
(-# or in P5G 'roup. )n t!e o@er+ll met+7+n+l2i o? (-#, 1> *5P 4ere +o$i+te"
(P K 10
H5
; t4o +t PRNP, t!ree +t ZBTB38RASA2, nine +t nine ot!er in"epen"ent non7
PRNP lo$i), more t!+n 4oul" be eLpe$te" b2 $!+n$e. 5one o? t!e lo$i re$entl2 i"enti?ie"
+ 'enome74i"e i'ni?i$+nt in tu"ie o? ot!er neuro"e'ener+ti@e "ie+e !o4e" +n2
$le+r e@i"en$e o? +o$i+tion in prion "ie+e. (on$ernin' $ommon 'eneti$ @+ri+tion, it
i li0el2 t!+t t!e PRNP lo$u $ont+in t!e onl2 tron' ri0 ?+$tor t!+t +$t uni@er+ll2
+$ro !um+n prion "ie+e. Eur "+t+ +re mot $onitent 4it! e@er+l ot!er ri0 lo$i o?
mo"et o@er+ll e??e$t 4!i$! 4ill reDuire ?urt!er 'eneti$ +o$i+tion tu"ie to pro@i"e
"e?initi@e e@i"en$e.
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INT!"#$TI!N
Prion "ie+e +re pro'rei@e neuro"e'ener+ti@e $on"ition o? !um+n +n" +nim+l
$+ue" b2 t!e mi?ol"in' +n" +''re'+tion o? t!e prion protein (PrP) (1). 1!e mot
$ommon !um+n prion "ie+e i por+"i$ or $l+i$+l (reut<?el"t-+0ob "ie+e ((-#)
4!i$! li0e ot!er por+"i$ neuro"e'ener+ti@e "ior"er o$$ur 4it! in$re+in' in$i"en$e
in ol"er +"ult. #epite "e$+"e o? in@eti'+tion, no $onitent ri0 ?+$tor ?or (-# !+@e
been i"enti?ie" +i"e ?rom +'e +n" $ommon 'eneti$ @+ri+tion +t t!e !um+n PrP 'ene
(PRNP). Hum+n prion "ie+e $omprie t!ree +etiolo'ie: +$Duire", in!erite" +n"
por+"i$. ;!ile le $ommon, +$Duire" prion "ie+e +re import+nt be$+ue o? publi$
!e+lt! $on$ern, u$! + t!oe ?ollo4in' t!e tr+nmiion o? t!e $+ttle prion "ie+e,
bo@ine pon'i?orm en$ep!+lop+t!2, to pre"omin+ntl2 2oun' /riti! +"ult + @+ri+nt
(reut<?el"t-+0ob "ie+e (@(-#) (2>).
A $ommon +mino7+$i" pol2morp!im +t $o"on 129 o? PRNP, en$o"in' eit!er met!ionine
or @+line, i + tron' 'eneti$ ri0 ?+$tor or mo"i?ier o? t!e $lini$op+t!olo'i$+l p!enot2pe
in +ll t2pe o? prion "ie+e (58). (o"on 127 +n" 219 +lo !+rbour +mino7+$i"
pol2morp!im 4!i$! $on?er reit+n$e to eit!er 0uru or (-# (9,10). Alt!ou'! t!ee +re
po4er?ul e??e$t, t!e tr+nmiibilit2 o? prion "ie+e in l+bor+tor2 ro"ent +llo4 ?or
'eneti$ m+ppin' tu"ie 4!i$! !+@e "emontr+te" e@er+l non7Prnp mo"i?ier lo$i (11
1%). P+r+llel !um+n tu"ie !+@e +lo be'un to u''et prion "ie+e ri0 'ene b+e" on
$+n"i"+te "eri@e" ?rom $loe ?un$tion+l lin0 to PrP, $reenin' !um+n 'ene ort!olo'ou
to moue $+n"i"+te, or 'enome74i"e +o$i+tion tu"ie (G;A*) in @(-#; eL+mple
in$lu"e t!e RARBTHRB lo$u (1>) +n" SPRN in @(-# (15); +n" HECTD2 (16) +n"
STMN2 (1>) in e@er+l !um+n prion "ie+e. 1!ee !um+n tu"ie 4ere un"erpo4ere"
b2 t!e ne$e+ril2 m+ll +mple i<e o? @(-# +n" t!e r+rit2 o? prion "ie+e in 'ener+l.
M+n2 o? t!e neuro"e'ener+ti@e "ie+e !+re ?un"+ment+l me$!+nim in@ol@in'
protein mi?ol"in' +n" prion7li0e pre+"in' o? p+t!olo'2 +o$i+te" 4it! +bnorm+ll2
+''re'+te" protein in br+in tiue (17,18). *u$! !+re" me$!+nim mi'!t impli$+te
Moint 'eneti$ ri0 ?+$tor. A e@er+l G;A* !+@e i"enti?ie" $+u+l lo$i in Al<!eimerN
"ie+e, ?rontotempor+l "ementi+, P+r0inonN "ie+e +n" +m2otrop!i$ l+ter+l $leroi
(1922), tetin' t!ee in prion "ie+e m+2 pro@i"e ini'!t into "ie+e me$!+nim
more bro+"l2.
Here, 4e preent t!e ?irt l+r'e G;A* in !um+n prion "ie+e b+e" on 2000 +mple
?rom t!ree popul+tion +n" rele@+nt publi$l2 +@+il+ble $ontrol erie. )n + in'le7t+'e
"ei'n, 4e 'enot2pe" 579 (-#, 1%% @(-#, 1%7 in!erite" prion "ie+e ()P#) +n" %2
i+tro'eni$ (reut<?el"t-+0ob "ie+e (i(-#) ?rom t!e .6; 680 (-# ?rom Germ+n2; +n"
568 +mple ?rom P+pu+ 5e4 Guine+ (P5G) in$lu"in' 0uru +n" el"erl2 ?em+le ur@i@or
o? t!e 0uru epi"emi$. 1!e ;1((( (.6) or 6E8A (Germ+n) pro@i"e" 6507 $ontrol
(2%). Ao$i+tion +n+l2e $on?irm t!e "omin+n$e o? PRNP + + ri0 ?+$tor rel+ti@e to +ll
ot!er 'ene. ;e +re +ble to pro@i"e e@i"en$e ?or e@er+l +""ition+l 'eneti$ ri0 ?+$tor
+lt!ou'! none o? t!ee +$!ie@e" 'enome74i"e i'ni?i$+n$e in met+7+n+l2e bet4een
re'ion or +etiolo'ie.
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%&#'T&
A?ter Du+lit2 $ontrol (O(), 8015 +mple 4ere +n+l2e" (ee M+teri+l +n" met!o").
Ao$i+tion +n+l2i 4+ ?irt "one in in"i@i"u+l +etiolo'i$+l 'roup +n" 'eo'r+p!i$+l
re'ion; t!ee 4ere t!en $ombine" in met+7+n+l2e. 1!e pre"etermine" prim+r2 tu"2
4+ + met+7+n+l2i o? !um+n prion "ie+e (+lleli$ tet, $+e$ontrol "ei'n, (-#,
@(-#, reit+n$e to 0uru) ?rom +ll 'eo'r+p!i$+l re'ion. Et!er $ombin+tion +n"
in"i@i"u+l +etiolo'i$+l +n" 'eo'r+p!i$+l tet 4ere e$on"+r2 out$ome, ?or eL+mple, +ll
(-#, (-# +n" @(-# in .6, (-# (.6 or Germ+n +lone), @(-#, 0uru (+'e o? "e+t!),
reit+n$e to 0uru, )P# (+'e o? onet), +n" (-# (+'e o? onet). A + l+r'e proportion o?
t!e Pore popul+tion 4ere +??e$te" b2 0uru in$lu"in' t!oe 4it! +pp+rent 'eneti$
reit+n$e +t PRNP, 4e !2pot!ei<e" t!+t $+e$ontrol tu"2 4oul" not be t!e bet
tr+te'2 +n" inte+" 0uru +'e o? "e+t! 4+ ue" + + Du+ntit+ti@e tr+it. A'e o? "e+t! in
0uru i i'ni?i$+ntl2 ol"er in PRNP $o"on 129 !etero<2'ou in"i@i"u+l $omp+re" 4it!
!omo<2'ou in"i@i"u+l (2>). A imil+r e??e$t i een ?or e@er+l )P#, +n" in + imil+r
4+2, +'e 4+ ue" + + Du+ntit+ti@e tr+it (2527).
)n t!e o@er+ll met+7+n+l2i o? +lleli$ tet, t!e top7r+n0e" +o$i+tion 4+ t!e 0no4n
+mino7+$i" pol2morp!im +t PRNP $o"on 129 r1799990 Io@er+ll P F 6.58 G 10
H7
, o""
r+tio (E8) F 0.77; in (-# 'roup, P F 1.2> G 10
H8
;1+ble 1J; !o4e@er, t!ere 4+
$oni"er+ble !etero'eneit2 bet4een t!e .6 +n" Germ+n2 prob+bl2 be$+ue o? $+e
+$ert+inment (.6, E8 F 0.8>; Germ+n2, E8 F 0.60, !i'!l2 i'ni?i$+nt "i??eren$e !o4n
4it! t!e ue o? + (o$!r+nM+ntelH+en<el tet ?or + 2 G 2 G 2 t+ble +n" /relo47#+2
tet o? !omo'eneit2 implemente" uin' P3)56) (Pi'. 1). 5ot+bl2, in e@er+l prion
"ie+e, r1799990 $on?er reit+n$e in t!e !etero<2'ou t+te; t!ere?ore, +n +lleli$
mo"el "oe not optim+ll2 $+pture t!e i'n+l +t t!i lo$u. 1!ree ot!er *5P 4ere
+o$i+te" 4it! t!e PRNP lo$u in (-# +t P K 10
H5
: r2756271, r6107516 +n"
r6116>77. :+$! o? t!ee *5P !+" lin0+'e "ieDuilibrium (3#) 4it! r1799990 r
2
Q 0.%,
+n" $on"ition+l or tr+ti?ie" +n+l2e u''ete" t!+t t!e entire +o$i+tion i'n+l 4+
$on?erre" b2 r1799990. Alt!ou'! t!e prim+r2 +n+l2i ue" +n +lleli$ mo"el, + 'enot2pi$
mo"el !o4e" + mu$! tron'er i'n+l, + eLpe$te"; ?or eL+mple, +t r1799990 in .6
(-#, P'enoF %.85 G 10
H25
+n" in Germ+n (-#, P'enoF 2.51 G 10
H%1
, 4it! + "e?i$it o?
!etero<2'ou 'enot2pe $onitent 4it! t!e 0no4n prote$ti@e e??e$t +t t!i lo$u (6).
(ontr+r2 to ot!er tu"ie, t!i G;A* pro@i"e" no e@i"en$e o? +""ition+l ri0 +t t!e lo$u
in (-# (1>,28%0). *5P r2756271 4+ 'enot2pe" in t!e $urrent tu"2 +n" !o4e" @er2
!i'! 3# 4it! *5P r102927% (r
2
F 0.9>) 'enot2pe" in pre@iou tu"ie in .6 (-# $+e
(1>,28%0). (on"ition+l +n+l2i b+e" on r2756271r1799990 !+plot2pe ?reDuen$ie
in $+e +n" $ontrol !o4e" no e@i"en$e ?or +""ition+l ri0 $on?erre" (r2756271
r1799990 !+plot2pe E8, AA F 1.>19, GA F 1.%8>, P F 0.65, implemente" 4it! P3)56).
1+ble 1.
1op r+n0e" +o$i+tion or"ere" b2 P7@+lue b+e" on met+7+n+l2i o? @(-#, (-# +n"
0uru reit+n$e
Pi'ure 1.
M+n!+tt+n plot !o4in' P7@+lue ?rom +lleli$ (1 ".?.) +n" 'enot2pi$ (2 ".?.) $!i7Du+re"
tet ?or ?i@e G;A* tu"ie in@ol@in' (A) @(-# @eru .6 $ontrol (;1(((2), (() .6
(-# @eru .6 $ontrol, ($) Germ+n (-# @eru Germ+n $ontrol (6E8A), (") 0uru
)))
Ai"e ?rom t!e PRNP lo$u, t!ere 4ere no 'enome74i"e i'ni?i$+nt +o$i+tion in t!e
pre"etermine" met+7+n+l2i o? +ll !um+n prion "ie+e; !o4e@er, ot!er lo$i "i" pro@i"e
e@i"en$e o? +o$i+tion in in"i@i"u+l +etiolo'i$+l $+te'orie or re'ion. 1!e top non7
PRNP lo$u 4+ +t ZBTB38RASA2 on $!romoome % (Pi'. 2) 4it! r9857275 (P F 1.5%
G 10
H6
, E8 F 0.7817), r1%095>5% +n" r678507% (P K 10
H5
). )n t!e .6, +ll (-# +n+l2i,
t!e top7r+n0e" +o$i+tion +i"e ?rom PRNP, 4+ +t t!e ZBTB38RASA2 lo$u, r295%01
(P F %.1% G 10
H8
, E8 F 0.70; (-#: P F %.7% G 10
H6
, E8 F 0.72; @(-#: P F 0.001>, E8 F
0.628>); !o4e@er, t!i *5P !o4e" no e@i"en$e o? +o$i+tion in Germ+n (-# or in
P5G. 1!ee *5P !+@e p+ir4ie 3# (r
2
Q 0.%) o@er %00 0b on $!romoome % (Pi'. 2).
8295%01 +lo !o4e" 4e+0 e@i"en$e o? + mo"i?2in' e??e$t on +'e o? onet o? (-# (+
+ Du+ntit+ti@e tr+it) 4it! t!e ri0 +llele bein' +o$i+te" 4it! +n e+rlier +'e o? onet (P F
0.0>).
Pi'ure 2.
)llutr+tion o? +o$i+tion i'n+l ?rom t!e top t4o +o$i+te" 'eneti$ lo$i in t!i tu"2
(.6 +n" Germ+n (-# met+7+n+l2i; P85P lo$u, top; A/1/%8 lo$u, bottom). H3o'10
P i !o4n ?rom +n +lleli$ tet uin' bot! 'enot2pe" +n" impute" *5P )))
Et!er lo$i (P K 10
H5
) in t!e prim+r2 tu"2 met+7+n+l2i +re !o4n in 1+ble 1. )n tot+l, 1>
*5P 4ere +o$i+te", P K 10
H5
(2 +t PRNP +n" 12 *5P +t 10 in"epen"ent non7PRNP
lo$i). ;e eL+mine" 4!et!er 4e ?oun" +n eL$e o? P K 10
H5
in t!ree 4+2. Pirt, b2
permutin' t!e $+e$ontrol t+tu o? +ll ub'roup $ontributin' to t!e met+7+n+l2i (ee
M+teri+l +n" met!o"), 4e ?oun" Q1% *5P on 8&500 permut+tion (R7Poion ?itte" P F
0.01>) +n" Q11 *5P on 19&500 permut+tion (R7Poion P F 0.0%8). *e$on", t!e
binomi+l prob+bilit2 o? Q1% *5P (P K 10
H5
) (n F 511862 tet) 4+ P F 0.001 +n" Q11
*5P 4+ P F 0.007; 4e +lo +$$ounte" ?or 3# b2 etim+tin' t!e e??e$ti@e number o?
in"epen"ent tet (ee M+teri+l +n" met!o"), Q9 in"epen"ent lo$i (n F %7>9>%) P F
0.005 +n" Q10 in"epen"ent lo$i P F 0.002. Pin+ll2, t!e Q7@+lue 4+ 0.%% ?or +ll 1> *5P,
P K 10
H5
(ee M+teri+l +n" met!o"). 5one o? t!ee lo$i !o4e" +n2 e@i"en$e o?
+o$i+tion in 0uru, 0uru reit+n$e, or )P# ("+t+ not !o4n). Alt!ou'! e@er+l *5P
4ere not pol2morp!i$ in t!e Pore popul+tion, t!ere 4ere no +o$i+tion i'n+l (P K 0.01)
"ete$te" +t t!ee lo$i S50 0b.
)n t!e in"i@i"u+l "ie+e $+te'orie, t!ere 4+ onl2 one non7PRNP ?in"in' +t +roun"
le@el o? 'enome74i"e i'ni?i$+n$e in t!e CHN2 'ene in @(-#, r1016726, P F 1.5 G
10
H7
(E8, 2.%6), +n" m+r'in+ll2 in .6 (-# P F 0.0>9 (E8, 1.2>), but not Germ+n (-#
or in P5G 'roup. Ao$i+tion pre@ioul2 "e$ribe" +t t!e RARBTHRB lo$u +n"
uptre+m o? STMN2 4ere unurpriin'l2 imil+r but not tron'er t!+n t!oe +lre+"2
publi!e" + t!ere 4+ +n +lmot $omplete o@erl+p in @(-# +mple 4it! t!e $urrent
tu"2 (1>). All ot!er "ie+e $+te'orie !o4e" no *5P, P K 10
H6
.
.nli0e @(-#, (-# i + !etero'eneou $on"ition $+ue" b2 multiple prion tr+in t2pe
(%1). ;e t!ere?ore ou'!t to eLplore e@i"en$e o? +o$i+tion in "e?ine" ub'roup o?
(-#. 1!e $o"on 129 pol2morp!im (r1799990) i + po4er?ul "etermin+nt o? tr+in
ele$tion (%2); !o4e@er, 4e ?oun" no e@i"en$e o? +n inter+$tion bet4een t!ee 10 lo$i
+n" r1799990. *tr+ti?i$+tion +t r1799990 "i" not tren't!en +n2 o? t!e top +o$i+tion
or re@e+l +n2 ne4 lo$i (P K 10
H6
). Prion tr+in +re 0no4n to "etermine 0e2 $lini$+l
?e+ture u$! + +'e o? onet but no 'enome74i"e i'ni?i$+nt lo$i 4ere i"enti?ie" 4!en
tetin' onl2 (-# preentin' prior to +'e 60.
6no4n 'enome74i"e i'ni?i$+nt +o$i+tion in rel+te" neuro"e'ener+ti@e $on"ition
!o4e" no $le+r7$ut e@i"en$e o? +o$i+tion in + imil+r "ire$tion in prion "ie+e
(Pi'. %). 82102808 +t STK39 !o4e" +n +o$i+tion 4it! tron'er e??e$t t!+n t!+t
"e$ribe" ?or P+r0inonN "ie+e in @(-#, .6 (-# +n" Germ+n (-# 4it! imil+r E8
in +ll 'roup (Pi'. %, *upplement+r2 M+teri+l, 1+ble *1).
Pi'ure %.
*tren't! o? +o$i+tion +t lo$i 0no4n to be in@ol@e" in ot!er neuro"e'ener+ti@e "ie+e.
#ot re?er to etim+te o? E8 ?rom t!e top7r+n0e" *5P in publi!e" +o$i+tion tu"ie
o? +ltern+ti@e neuro"e'ener+ti@e "ie+e (ee *upplement+r2 M+teri+l, 1+ble )))
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"I&$#&&I!N
;e report t!e ?irt G;A* o? (-# +n" 0uru +n" t!e ?irt tu"2 po4ere" to "ete$t
mo"er+tel2 tron' ri0 lo$i in !um+n prion "ie+e (E8 Q 1.5). ;e $oni"ere" e@er+l
"i??erent !2pot!ee o? 'eneti$ ri0, in$lu"in' 4!et!er e??e$t 4ere "ie+e ubt2pe or
re'ion pe$i?i$, +n" 4!et!er poible ri0 +llele mo"i?2 $lini$+l p!enot2pe. )n 2009, 4e
publi!e" ?in"in' ?rom + G;A* in @(-#, u''etin' *5P uptre+m o? t!e RARB +n"
STMN2 lo$i 4ere $+n"i"+te ?or @(-# +o$i+tion; !o4e@er, t!i tu"2 4+ onl2 po4ere"
to "ete$t @er2 tron' e??e$t "i$o@ere" in @(-# (1>). .nurpriin'l2, in t!e $urrent
tu"2, PRNP 'enot2pe 4ere tron'l2 +o$i+te" 4it! ri0 in +ll "ie+e $+te'orie +n"
re'ion. 5o ot!er lo$u !o4e" + imil+rl2 tron' or uni@er+l +o$i+tion. )n t!e met+7
+n+l2i, !o4e@er, 10 ot!er lo$i 4ere ?oun" to +ppro+$! t!e t+titi$+l t!re!ol" ?or
u''eti@e G;A* i'ni?i$+n$e (P K 10
H5
), be2on" t!e number eLpe$te" b2 $!+n$e,
$onitent 4it! e@er+l mo"et 'eneti$ e??e$t. Purt!er 'eneti$ +n+l2e +re reDuire" to
pro@i"e $on@in$in' e@i"en$e ?or +o$i+tion +t t!ee lo$i. ;e +lo "emontr+te t!+t it i
?e+ible to $on"u$t G;A* on ol" "e'r+"e" +n" +mpli?ie" #5A in t!e 0uru +r$!i@e
$olle$tion.
A 4e+lt! o? e@i"en$e pl+$e PrP $entr+ll2 in t!e p+t!o'enei o? +ll prion "ie+e. 1!e
'eneti$ +o$i+tion +t PRNP 4+ @er2 tron' +n" preent +$ro re'ion, "ie+e ubt2pe
+n" $lini$+l p!enot2pe +lbeit 4it! "i??erent 'eneti$ mo"el in +etiolo'i$+l ub'roup. Por
eL+mple, in @(-#, +ll but one +mple 4+ !omo<2'ou A (en$o"in' met!ionine) +t
r1799990 ($o"on 129), 4!ere+ bot! !omo<2'ou 'enot2pe 4ere +t in$re+e" ri0
rel+ti@e to !etero<2'ou in +ll ot!er "ie+e 'roup.
*e@er+l tu"ie !+@e reporte" +""ition+l 4e+0 +o$i+tion 4it! (-# or @(-# +t t!e
PRNP lo$u be2on" t!+t $on?erre" b2 r1799990 or ot!er miene pol2morp!im
(1>,28%0). )n t!i tu"2, our $on"ition+l +n+l2e "i" not upport t!ee ?in"in' 4it! no
e@i"en$e ?or +""ition+l ?+$tor; poible eLpl+n+tion in$lu"e "i??erent *5P 'enot2pe"
(+lt!ou'! 4e !+@e !o4n t!e 'enot2pe" *5P 4+ +n eL$ellent urro'+te ?or + pre@ioul2
reporte" ri0 +llele), t!e ?+ilure o? imput+tion to +$$ur+tel2 'enot2pe ot!er *5P, +n"
?+le poiti@e or ?+le ne'+ti@e +o$i+tion. 1!i tu"2 u''et t!+t +""ition+l
+o$i+tion +t t!e PRNP lo$u, i? preent, i li0el2 to be o? mo"et e??e$t o@er+ll.
*e@er+l ot!er lo$i +ppro+$!e" 'enome74i"e i'ni?i$+n$e in o@er+ll met+7+n+l2i. *ome
o? t!ee lo$i +re in t!e @i$init2 o? 'ene t!+t mi'!t be pl+uible biolo'i$+l $+n"i"+te ?or
$on?errin' ri0 o? prion "ie+e, ot!er +re in 'ene7"ene re'ion or 'ene "eert. Por
eL+mple, r9857275, top r+n0e" in t!e met+7+n+l2i, i introni$ to ZBTB38, + <in$ ?in'er
tr+n$ription+l +$ti@+tor t!+t bin" met!2l+te" #5A, i eLpree" in br+in +n" e@er+l
*5P in t!e 'ene +re +o$i+te" 4it! +"ult !ei'!t in multiple popul+tion (%%). *e$on"
r+n0e" in t!e o@er+ll met+7+n+l2i 4+ r>88%%%, uptre+m o? *:MA%A, + e$rete"
protein 4it! $!emo+ttr+$ti@e or repuli@e ?un$tion u$! + t!e in!ibition o? +Lon+l
out'ro4t! or timul+tion o? t!e 'ro4t! o? +pi$+l "en"rite. Et!er lo$i (P K 10
H5
) in 'ene7
"ene re'ion or "eert m+0e it "i??i$ult to 'ener+te !2pot!ee o? + poible me$!+nim.
1!e priorit2 ?or ?uture 4or0 i to 'ener+te robut 'enome74i"e t+titi$+l i'ni?i$+n$e b2
repli$+tion tu"2 in (-# ?rom ot!er popul+tion.
*e@er+l 'ene !+@e +lre+"2 been propoe" + prion "ie+e ri0 ?+$tor, in$lu"in' t!oe +t
t!e RARBTHRB lo$u, uptre+m o? STMN2 +n" in t!e HECTD2 +n" SPRN 'ene. 1!e
met+7+n+l2i +$ro +ll prion "ie+e pro@i"e" no +""ition+l upport ?or t!ee
propo+l; !o4e@er, t!i i not urpriin' + +ll o? t!ee report 4ere !etero'enou +$ro
"i??erent +etiolo'i$+l 'roup. ;e +lo $oni"ere" 4!et!er +o$i+tion in ot!er rel+te"
neuro"e'ener+ti@e "ie+e mi'!t be ?oun" in prion "ie+e, ?or eL+mple, APOE, CLU,
PICALM, BIN1 +n" t!e BLOC1S3 lo$u in Al<!eimerN "ie+e; MAPT, SNCA, LRRK2
+n" GBA in P+r0inonN "ie+e; +n" t!e (!r 9p21 lo$u in A3*; !o4e@er, 4e ?oun" no
e@i"en$e o? e@en mo"et +o$i+tion +t t!ee *5P +i"e ?rom @er2 mo"et e??e$t +t
STK39. 1!ee "+t+ u''et t!+t t!ee 'eneti$ p+t!4+2 impli$+te" in ot!er
neuro"e'ener+ti@e "ie+e +re not 'ener+ll2 !+re" or import+nt in prion "ie+e.
E@er+ll our reult +re open to e@er+l "i??erent interpret+tion. Ai"e ?rom PRNP, ot!er
'eneti$ ?+$tor m+2 be 4e+0 in prion "ie+e. Prion "ie+e +re r+re, +n" + + reult,
t!ere i limite" e@i"en$e re'+r"in' !erit+bilit2. )n?eren$e o? 'eneti$ u$eptibilit2 m+2 be
m+"e ?rom iblin' $on$urren$e (%>), t!e !erit+bilit2 o? +'e o? onet in "i??erent )P#
(27), +n" b2 eLtr+pol+tion ?rom t!e $le+r e@i"en$e ?or 'eneti$ mo"i?ier in moue tu"ie
(12). :pi"emiolo'i$+l tu"ie !+@e i"enti?ie" no mo"i?i+ble ri0 ?+$tor, +i"e ?rom
in$onitent report o? +n +o$i+tion 4it! p+t ur'er2 (%5). 1!e +etiolo'2 o? (-#
t!ere?ore rem+in ob$ure to !um+n tu"ie, + moue tu"ie mo"el +$Duire" r+t!er t!+n
por+"i$ prion "ie+e.
Alt!ou'! t!e onl2 'eneti$ ri0 ?+$tor i"enti?ie" in t!i tu"2 4+ $o"on 129 o? PRNP, it
4oul" be prem+ture to $on$lu"e t!+t no ot!er protein +re in@ol@e" in mo"i?2in' t!e ri0
o? "ie+e. )n $omp+rion 4it! u$$e?ul G;A* in $ommon "ie+e, t!e +mple i<e
4e !+@e +n+l2e" rem+in mo"et +n" 4e+0 e??e$t 4oul" not be "ete$te". ;e !+@e not
$oni"ere" $op2 number @+ri+tion or r+re *5P 4!i$! m+2 $on?er tron' e??e$t. Et!er
eLpl+n+tion o? t!e l+$0 o? +o$i+tion in (-# in$lu"e t!e !etero'eneit2 o? t!i "ie+e
"e?ine" b2 + $lini$+l 2n"rome. *e@er+l +etiolo'ie +re poible in t!e 'roup in$lu"in' +
proportion o? <oonoti$ or i+tro'eni$ "ie+e. :+$! o? t!ee $+ue $oul" !+@e pe$i?i$
'eneti$ ri0 ?+$tor t!+t 4oul" be "ilute" in + tu"2 un+ble to $orre$tl2 +$ert+in
+etiolo'2. Pin+ll2, it i poible t!+t om+ti$ mut+tion or to$!+ti$ (protein7b+e") e@ent
+re $entr+l to +etiolo'2 +n" 'eneti$ mo"i?ier pl+2 onl2 + @er2 m+ll role in t!e
"o4ntre+m ri0 o? $lini$+l "ie+e.
Puture 4or0 !oul" prioriti<e ?urt!er G;A* in "i??erent popul+tion +n" tu"ie "ei'ne"
to +$ert+in r+rer *5P 4it! poibl2 l+r'er ?un$tion+l e??e$t, +n+l2i o? $op2 number
@+ri+tion, p+t!4+2 +n+l2i +n" ?urt!er tu"2 o? t!e mo"i?i$+tion o? $lini$+l p!enot2pe b2
'eneti$ pol2morp!im.
Go to:
*AT%IA'& AN" *%T+!"&
+uman samples
1!e $lini$+l +n" l+bor+tor2 tu"ie 4ere +ppro@e" b2 t!e lo$+l ree+r$! et!i$ $ommittee
o? .ni@erit2 (olle'e 3on"on )ntitute o? 5eurolo'2 +n" 5+tion+l Hopit+l ?or
5eurolo'2 +n" 5eurour'er2 +n" b2 t!e Me"i$+l 8ee+r$! A"@ior2 (ommittee o? t!e
Go@ernment o? P5G. Pull p+rti$ip+tion o? t!e P5G $ommunitie in@ol@e" 4+
et+bli!e" +n" m+int+ine" t!rou'! "i$uion 4it! @ill+'e le+"er, $ommunitie,
?+milie +n" in"i@i"u+l. A$$e to (-# p+tient 'enot2pe "+t+ i +@+il+ble t!rou'! t!e
:urope+n Genome7P!enome Ar$!i@e +t t!e :urope+n /ioin?orm+ti$ Ar$!i@e (+$$eion
number :GA*00000000097).
,ariant $reut-feldt.Jakob disease
Prob+ble or "e?inite @(-# p+tient, "i+'noe" +$$or"in' to et+bli!e" $riteri+
(!ttp:&&444.+"@ior2bo"ie."o!.'o@.u0&+$"p&te'ui"+n$e&te'ui"+n$eT+nneLb.p"?), 4ere
re$ruite" b2 t!e 5+tion+l Prion (lini$ (5P(), 3on"on or t!e 5+tion+l (-# 8ee+r$! +n"
*ur@eill+n$e .nit, :"inbur'!, ?rom 1995 to 2010. Genomi$ #5A 4+ uu+ll2 eLtr+$te"
?rom perip!er+l bloo"; br+in tiue 4+ ue" + + our$e ?or ome p+tient. Ampli?ie"
#5A, uin' eit!er multiple "ipl+$ement +mpli?i$+tion (Geneer@i$e, (+mbri"'e, .6) or
?r+'ment+tion7P(8 met!o" (GenomepleL, *i'm+), 4+ ue" ?or + m+ll number (K10U)
o? +mple. *+mple 4ere $!e$0e" ?or "e'r+"+tion on 1U +'+roe 'el +n" tore" +t 50
n'&Vl in 1ri7:#1A bu??er. All p+tient 4ere t!ou'!t to !+@e +$Duire" t!e "ie+e in t!e
.6. Me+n +'e o? "ie+e onet 4+ %0 2e+r, 56U 4ere m+le.
&poradic $reut-feldt.Jakob disease
Prob+ble or "e?inite .6 (-# p+tient, +$$or"in' to ;HE $riteri+, 4ere re$ruite" b2 t!e
5P(, 3on"on, t!e 5(-#8*., :"inbur'!, or numerou ot!er re?errer in t!e .6. #5A
4+ our$e" +n" +mpli?ie" + ?or @(-#. All p+tient 4ere o? .6 or nort!ern :urope+n
ori'in. Alt!ou'! t!e @+t m+Morit2 o? p+tient 4ere o? 4!ite7/riti! et!ni$it2, +n" +ll
p+tient o? 0no4n non74!ite et!ni$it2 4ere eL$lu"e", t!i in?orm+tion 4+ b+e" on
n+me +n" 'eo'r+p!2 ?or ome +mple. #5A prep+r+tion +n" tor+'e 4+ imil+r to
@(-#. )n t!e .6 61U !+" p+t!olo'i$+ll2 $on?irme" (-#, t!e rem+in"er !+" + "i+'noi
o? prob+ble (-# +$$or"in' to t!e publi!e" ;HE $riteri+ 4it! + !i'! pe$i?i$it2.
Me"i+n +'e o? onet o? "ie+e 4+ 65 2e+r (1587); 272 p+rti$ip+nt 4ere ?em+le. )n
Germ+n2, +ll $+e 4ere p+t!olo'i$+ll2 $on?irme", me"i+n +'e o? onet 4+ 66 (r+n'e
1990); %06 p+rti$ip+nt 4ere ?em+le.
/uru0elderly women resistant to kuru
Prior to 1987, 0uru ur@eill+n$e 4+ $on"u$te" b2 m+n2 "i??erent in@eti'+tor
(G+M"ue0, Ai'+, /+0er, Alper, Horn+broo0, Moir +n" ot!er) +n" ?rom 1987 to 1995
olel2 b2 t!e 6uru *ur@eill+n$e 1e+m o? t!e P5G )ntitute o? Me"i$+l 8ee+r$!. Prom
1996 on4+r", 0uru ur@eill+n$e 4+ tren't!ene" +n" + ?iel" b+e +n" b+i$ l+bor+tor2
?or +mple pro$ein' +n" tor+'e 4+ et+bli!e" in t!e @ill+'e o? ;+i+ in t!e *out!
Pore. 1!e 0uru $olle$tion $omprie" 2oun' $!il"ren, +"ole$ent +n" +"ult ?rom +roun"
t!e pe+0 o? t!e epi"emi$ +n" el"erl2 re$ent 0uru $+e 4it! lon' in$ub+tion time.
:l"erl2 eLpoe" 4omen 4ere "e?ine" + +'e" o@er 50 2e+r in 2000 ?rom + 0uru7eLpoe"
re'ion. 1!ee 4omen 4ere un+??e$te" +t t!e time o? +mplin' but 4ere t!ou'!t to !+@e
been eLpoe" to 0uru prion in $!il"!oo". Alt!ou'! t!ee 4omen m+2 not be trul2
Wreit+ntX to 0uru prion t!e2 4oul" !+@e in$ub+tion time in eL$e o? >0 2e+r.
A""ition+l $ontrol 4ere obt+ine" ?rom t!e 2oun' mo"ern "+2 !e+lt!2 popul+tion t!+t
!+ not been eLpoe" to 0uru but $+me ?rom @ill+'e in t!e eLpoe" re'ion b2 m+t$!in'
e+$! el"erl2 4om+n (Wreit+ntX) to +t le+t t4o $urrent rei"ent o? t!e +me @ill+'e +'e"
K50 in 2000. 1!ee l+r'el2 $+me ?rom t!e *out! Pore, but 4it! + i'ni?i$+nt number ?rom
t!e 5ort! Pore +n" + m+ll number o? in"i@i"u+l ?rom Gimi, 6ei+'+n+ +n" Y+'+ri+
lin'uiti$ 'roup. Purt!er $ontrol 4ere obt+ine" ?rom 2oun' uneLpoe" people ?rom
+re+ o? P5G 4!ere no 0uru !+ been re$or"e". ;!ere i"enti?ie" b2 eit!er 'ene+lo'i$+l
"+t+ or mi$ro+tellite +n+l2i, ?irt "e'ree rel+ti@e 4ere eL$lu"e" ?rom t!ee 'roup.
#5A ?rom "e'r+"e" +r$!i@+l 0uru er+, obt+ine" ?rom t!e 5)H $olle$tion, 4+ iol+te"
b2 O)AG:5 O)A+mp /loo" #5A mini0it ?ollo4e" b2 4!ole 'enome +mpli?i$+tion
eit!er t!rou'! uin' + Z29 proto$ol (Geneer@i$e) or GenomePleL (omplete ;!ole
Genome Ampli?i$+tion 6it (*i'm+).
1uality control
1ot+ll2, 8>0 6E8A $ontrol 4ere 'enot2pe" on 5506 )llumin+ +rr+2 +n" 5667
;1(((2 $ontrol on t!e )llumin+ 1.2M (utom #uo +rr+2; $+e 4ere 'enot2pe" on t!e
)llumin+ 6606. (+e in$lu"e" 680 Germ+n (-# +mple, 579 .6 (-#, 1%% .6 @(-#
(+n" 5 non7.6 @(-#), 165 0uru +mple, 125 0uru reit+nt 4omen +n" 286
'eo'r+p!i$+ll2 m+t$!e" $ontrol in"i@i"u+l. 1!ere 4+ no "i$rep+n$2 bet4een reporte"
+n" 'eneti$ 'en"er in t!e $+e.
Prior to +n+l2i, +mple 4ere remo@e" ?rom t!e ;1(((2 "+t+ et b2 t!eir pre$ribe"
$riteri+. 1!e ;1(((2 $!oe $riteri+ to be imil+r to t!oe o?ten +pplie" + t+n"+r" in
G;A tu"ie. )n"i@i"u+l 4ere eL$lu"e" i? t!e2 "ipl+2e" + "iproportion+te number o?
!etero<2'ou or miin' $+ll. 8el+te" in"i@i"u+l 4ere eL$lu"e" +$$or"in' to i"entit2 b2
"e$ent ()/#). )n"i@i"u+l 4ere eL$lu"e" on t!e b+i o? +n$etr2 i? t!e2 "i??ere" ?rom
t!e m+Morit2 o? t!e $olle$tion +$$or"in' to + prin$iple $omponent +n+l2i o? H+pM+p
in"i@i"u+l. Gen"er "i$rep+n$2 bet4een t!e upplier +n" t!e in?erre" 'en"er +lo le" to
+mple remo@+l. )n"i@i"u+l 4ere eL$lu"e" i? t!e me+n o? t!eir A +n" / +llele intenitie
4ere outlier 4!en $omp+re" 4it! t!e +mple +t l+r'e. )n tot+l, >67 ;1(((2 in"i@i"u+l
4ere remo@e" le+@in' 5200 +mple $omprie" o? 26%0 m+le +n" 2570 ?em+le.
;e ue" + 98U +mple 'enot2pin' $+ll t!re!ol" ?or t!e m+in +o$i+tion tet; !o4e@er,
+n 80U +mple $+ll r+te 4+ +pplie" to t!e 0uru +mple. 1!i +llo4e" u to ret+in 90U
o? t!i m+ll +n" uniDue $+e erie. Eber@+tion o? $on$or"+n$e bet4een 0no4n
"upli$+te p+ir (n F 8) "emontr+te" t!+t t!e o@er+ll 'enot2pe error 4+ K0.00085 4it! +
+mple $+ll r+te +bo@e 80U. An+l2e uin' 0uru +mple 4ere retri$te" to t!i
+etiolo'i$+l 'roup +lone uin' +'e +t "e+t! + + Du+ntit+ti@e tr+it to minimi<e t!e
poibilit2 o? intro"u$in' bi+ b2 $omp+rin' $o!ort 4it! "i??erent O(. (r2pti$
"upli$+te 4ere i"enti?ie" uin' t!e t+titi$+l 'eneti$ me+ure o? rel+te"ne, pi7!+t. 1!e
t!re!ol" ?or eL$luion 4+ pi7!+t Q 0.8. A ubet o? 2006 *5P $ommon to +ll t!ree
+rr+2 +n" ele$te" ?or t!e !i'!et minor +llele ?reDuen$2 (MAP) 4ere ue" to "eri@e pi7
!+t etim+te. Enl2 $r2pti$ "upli$+te 4ere "i$o@ere" +n" no !i'!l2 rel+te" in"i@i"u+l.
*tep 4ere t+0en to i"enti?2 et!ni$ outlier 4it!in t!e +mple et. A ?or t!e pi7!+t
etim+te, t!e +me 2006 *5P 4ere ue" to "eri@e i"entit2 b2 t+te etim+te 4!i$!
4ere plotte" on t!e ?irt t4o +Le o? + multi7"imenion+l $+lin' plot. *+mple outi"e
t!e m+in $luter 4ere eL$lu"e". ;!ole 'enome +mpli?ie" +mple "i" not +ppe+r +
outlier +n" o 4ere ret+ine". A?ter +mple O(, 815 6E8A, 6%> Germ+n (-#, 522
.6(-# +n" 125 .6@(-# +mple 4ere ret+ine" ?or +n+l2i. Pi@e pre@ioul2 0no4n
non7.6 @(-# +mple +ppe+re" outi"e t!e m+in $luter.
OO plot +n" 'enomi$ $ontrol in"i$+te" mo"et or no in?l+tion o? t!e +o$i+tion tet
t+titi$ in +ll eL$ept t!e Germ+n tu"2 (l+mb"+, .6 @(-# F 1; .6 (-# F 1.02;
Germ+n (-# F 1.12; Pore F 0.99) (ee *upplement+r2 M+teri+l, Pi'ure *1). ;e "i" not
?in" e@i"en$e o? te$!ni$+l +rte?+$t rel+te" to t!e ue o? "i??erent 'enot2pin' +rr+2
(t!rou'! eL+min+tion o? OO plot o? *5P 4it! "i??erent +llele ?reDuen$ie, "i??erenti+l
miin'ne +n" H+r"2;einber' eDuilibrium, or +o$i+tion 4it! 'enot2pin' b+t$!e).
;e $on$lu"e" t!+t popul+tion tr+ti?i$+tion 4+ t!e mot li0el2 eLpl+n+tion. (orre$tion
uin' prin$iple $omponent (:i'entr+t) re"u$e" l+mb"+ in t!e Germ+n tu"2 ?rom 1.11
to 1.0%7. Por met+7+n+l2i, Germ+n P7@+lue +n" E8 t+n"+r" error 4ere $orre$te" b2
t!e 'enomi$ $ontrol (G() met!o" (ee *upplement+r2 M+teri+l, Pi'ure *1) (%6). Allele
?reDuen$ie 4ere m+r0e"l2 "i??erent in t!e P5G popul+tion + eLpe$te", +n" o +
"i??erent et o? 1756 *5P 4+ +pplie" to t!e P5G +mple. 5o P5G +mple 4ere
remo@e" + et!ni$ outlier.
*5P O( 4+ +pplie" to t!e $ontrol "+t+ to'et!er 4it! t!e $+e. *5P 4it! + miin'ne
Q 1U; MAP K 1U, or !o4in' "ep+rture ?rom H+r"2;einber' eDuilibrium in $ontrol
(P K 1 G 10
H%
) 4ere eL$lu"e". *5P to be eL$lu"e" @+rie" "epen"in' upon t!e
$omp+rion bein' m+"e. A eLpe$te" t!e m+Morit2 o? *5P eL$lu"e" in t!e P5G
$omp+rion 4ere "ue to lo4 minor +llele ?reDuen$ie in t!e P5G popul+tion. *5P
r1799990 4+ miin' ?rom t!e 5506 6E8A $ontrol et +n" t!e 6606 $+e but 4+
preent on t!e 1.2M (utom #uo ;1(((2 $!ip. *5P r1799990 4+ 'enot2pe" ?or t!e
miin' +mple uin' +lleli$ "i$rimin+tion P(8 probe +n" t!e "+t+ +""e" to t!e "+t+
et. 1!i *5P p+e" +ll ot!er O( me+ure +n" o 4+ ret+ine" in t!e tu"2 to +llo4
tu"2 o? t!e PRNP +o$i+tion +n" tr+ti?i$+tion.
1!e 1000 Genome Pilot (-une 2010) [ H+pM+p% (Pebru+r2 2009) (:. p+nel 4+ ue"
to impute *5P 2.5 Mb uptre+m +n" "o4ntre+m o? our lo$i o? interet (mentione"
+bo@e). *5P 4ere tr+n" +li'ne" +n" p!+e", prior to imput+tion uin' t!e pro'r+m
)mputeT@2 4!i$! emplo2 + M+r0o@ $!+in Monte (+rlo ?r+me4or0 (%7). )mpute" *5P
4it! + miin'ne Q 1U; MAP K 1U, or !o4in' "ep+rture ?rom H+r"2;einber'
eDuilibrium in $ontrol (K1 G 10
H%
) 4ere eL$lu"e". *ubeDuent tet o? +o$i+tion 4ere
per?orme" uin' *5Ptet@2 4!i$! t+0e 'enot2pe improb+bilit2 into +$$ount 4!en
$omp+rin' impute" 'enot2pe (%8).
&tatistical analysis
#+t+ m+nipul+tion +n" t+titi$ 4ere per?orme" uin' P3)56 (%9). (o!ort o? @(-#,
.6 (-#, Germ+n (-#, i+tro'eni$ (-# +n" 0uru reit+nt 4omen 4ere $omp+re" 4it!
rele@+nt $ontrol uin' +lleli$ +n" 'enot2pi$ mo"el. A'e +t "e+t! (or +mplin') 4+ ue"
+ + Du+ntit+ti@e tr+it in +n+l2i o? 0uru p+tient. A'e +t $lini$+l onet eLpree" +
"e@i+tion ?rom t!e me+n eLpe$te" onet ?or e+$! )P# mut+tion 4+ ue" + + Du+ntit+ti@e
tr+it in t!e )P# $o!ort. Met+7+n+l2e 4ere "one uin' P3)56 ?or +ll .6 (-#, +ll (-#,
+ll (-# +n" +ll (-# in$lu"in' reit+n$e to 0uru. )mput+tion 4+ "one uin' )MP.1:2
uin' "+t+ pro@i"e" b2 t!e ;1((( +n" 1000 'enome proMe$t. (on"ition+l +n+l2e
4ere "one +t t!e PRNP lo$u uin' r1799990 in +""iti@e +n" 'enot2pi$ mo"el.
*tr+ti?ie" +n+l2e 4ere "one uin' +ll t!ree 'enot2pe +t r1799990. A'e o? $lini$+l
onet in .6 (-# 4+ ue" eit!er + + Du+ntit+ti@e tr+it or + + t!re!ol" ?or tr+ti?i$+tion
(in$lu"e onl2 (-# +'e +t onet K60 2e+r). ;e per?orme" + permut+tion +n+l2i to
e@+lu+te t!e i'ni?i$+n$e o? ober@in' n *5P 4it! P K 10
H5
, 4!en +pproLim+tel2 ?i@e
u$! *5P 4ere eLpe$te" un"er t!e null !2pot!ei. (+e$ontrol l+bel 4ere permute"
4it!in e+$! o? t!e ?our $o!ort, +n" + 'enome74i"e met+7+n+l2i 4+ per?orme" on t!e
permute" "+t+ et uin' t!e +me +n+l2i + ?or t!e ober@e" "+t+ et. 1!i 4+ repe+te"
500 time 'ener+tin' $ru"e etim+te ?or t!e i'ni?i$+n$e o? t!i t+titi$ (ee 8eult). 1o
impro@e on t!i etim+te, 4e ?itte" + '+mm+7Poion "itribution (+lo 0no4n + t!e
ne'+ti@e binomi+l) to t!e 500 $ount o? i'ni?i$+nt *5P b2 m+t$!in' t!e empiri$+l me+n
+n" @+ri+n$e to t!eir t!eoreti$+l @+lue (met!o" o? moment etim+tion). Alt!ou'! t!e
$!oi$e o? 10
H5
+ + i'ni?i$+n$e t!re!ol" ?or t!i +n+l2i i +rbitr+r2, it i + n+tur+l
$!oi$e +n" t!e onl2 one 4e $oni"ere" o 4e !+@e not implemente" +n2 ?orm+l
$orre$tion ?or multiple tetin'. ;e etim+te" t!e e??e$ti@e number o? in"epen"ent tet
uin' impleM (>0).
Go to:
&#PP'%*%NTA2 *AT%IA'
*upplement+r2 M+teri+l i +@+il+ble +t HMG online.
Go to:
3#N"ING
Pun"in' ?or t!e proMe$t 4+ pro@i"e" b2 t!e ;ell$ome 1rut +n" Me"i$+l 8ee+r$!
(oun$il. 1!e 0uru tu"ie 4ere initi+ll2 ?un"e" b2 + ;ell$ome 1rut Prin$ip+l 8ee+r$!
Pello4!ip in t!e (lini$+l *$ien$e to -.(., +n" in$e 2001, +ll ot!er +pe$t o? t!e 4or0
b2 t!e Me"i$+l 8ee+r$! (oun$il. *ome o? t!i 4or0 4+ un"ert+0en +t .(3H&.(3 4!o
re$ei@e" + proportion o? ?un"in' ?rom t!e #ep+rtment o? He+lt!N 5)H8 /iome"i$+l
8ee+r$! (entre ?un"in' $!eme.
Go to:
&upplementary *aterial
&upplementary "ata4
(li$0 !ere to @ie4.
Go to:
A$/N!5'%"G%*%NT&
1!i tu"2 m+0e ue o? "+t+ 'ener+te" b2 t!e ;ell$ome 1rut (+e7(ontrol (onortium.
A ?ull lit o? t!e in@eti'+tor 4!o $ontribute" to t!e 'ener+tion o? t!e "+t+ i +@+il+ble
?rom 444.4t$$$.or'.u0. ;e 4oul" li0e to t!+n0 p+tient, t!eir ?+milie +n" $+rer, .6
neurolo'it +n" ot!er re?errin' p!2i$i+n, $o74or0er +t t!e 5+tion+l Prion (lini$, our
$olle+'ue +t t!e 5+tion+l (reut<?el"t7-+0ob #ie+e 8ee+r$! +n" *ur@eill+n$e .nit,
:"inbur'!, +n" t!e Pore $ommunitie in P5G. ;e t!+n0 our te+m o? lo$+l 0uru reporter,
in$lu"in' 1uli Anu+, Au2+n+ ;in+'+i2+, t!e l+te Anu+ *en+@+i2o, )'+n+ Are+'u, 6+bin+
Y+r+0i, An"eron Pu4+, #+@i" P+0o, Pibi Au2+n+, -ol+m E@e, -+$0 6ointo, #+t+ Hutu
+n" -+me 6i+@+. ;e +re 'r+te?ul to Ant!on2 -+$0on +n" Peter *ib+, -o!n 8ee"er,
(!+rle M'one +n" ot!er t+?? o? t!e P5G )ntitute o? Me"i$+l 8ee+r$! ?or t!eir upport.
;e 'r+te?ull2 +$0no4le"'e t!e !elp o? t!e l+te (+rleton G+M"ue0, t!e l+te -oep! Gibb
+n" t!eir +o$i+te ?rom t!e ?ormer 3+bor+tor2 o? (entr+l 5er@ou *2tem *tu"ie o? t!e
5+tion+l )ntitute o? He+lt!, /et!e"+, .*A, ?or +r$!i@in' +n" !+rin' ol" 0uru +mple.
Genot2pe "+t+ 4ill be m+"e +@+il+ble t!rou'! t!e :urope+n Genome7p!enome Ar$!i@e.
Con!"#$% o In$&r&%$ %$'$&(&n$. 5one "e$l+re".
Go to:
%3%%N$%&
1. (ollin'e -. Prion "ie+e o? !um+n +n" +nim+l: t!eir $+ue +n" mole$ul+r b+i.
Annu. 8e@. 5euro$i. 2001;2>:519550. IPubMe"J
2. (ollin'e -., *i"le 6.(., Me+" -., )roni"e -., Hill A.P. Mole$ul+r +n+l2i o? prion
tr+in @+ri+tion +n" t!e +etiolo'2 o? Wne4 @+ri+ntX (-#. 5+ture. 1996;%8%:685690.
IPubMe"J
%. /ru$e M.:., ;ill 8.G., )roni"e -.;., M$(onnell )., #rummon" #., *uttie A.,
M$(+r"le 3., (!ree A., Hope -., /ir0ett (., et +l. 1r+nmiion to mi$e in"i$+te t!+t
Wne4 @+ri+ntX (-# i $+ue" b2 t!e /*: +'ent. 5+ture. 1997;%89:>98501. IPubMe"J
>. Hill A.P., #ebrul+i M., -oiner *., *i"le 6.(.3., Go4l+n" )., (ollin'e -. 1!e +me
prion tr+in $+ue @(-# +n" /*:. 5+ture. 1997;%89:>>8>50. IPubMe"J
5. (ollin'e -., P+lmer M.*., #r2"en A.-. Geneti$ pre"ipoition to i+tro'eni$ (reut<?el"t
-+0ob "ie+e. 3+n$et. 1991;%%7:1>>11>>2. IPubMe"J
6. P+lmer M.*., #r2"en A.-., Hu'!e -.1., (ollin'e -. Homo<2'ou prion protein
'enot2pe pre"ipoe to por+"i$ (reut<?el"t-+0ob "ie+e. 5+ture. 1991;%52:%>0%>2.
IPubMe"J
7. Poulter M., /+0er H.P., Prit! (.#., 3e+$! M., 3o?t!oue 8., 8i"le2 8.M., *!+! 1.,
E4en P., (ollin'e -., /ro4n -., et +l. )n!erite" prion "ie+e 4it! 1>> b+e p+ir 'ene
inertion: ): 'ene+lo'i$+l +n" mole$ul+r tu"ie. /r+in. 1992;115:675685. IPubMe"J
8. (ollin'e -. Mole$ul+r neurolo'2 o? prion "ie+e. -ourn+l o? 5eurolo'2 5eurour'er2
+n" P2$!i+tr2. 2005;76:906919. IPM( ?ree +rti$leJ IPubMe"J
9. Me+" *., ;!it?iel" -., Poulter M., *!+! P., .p!ill -., (+mpbell 1., Al #uM+il2 H.,
Hummeri$! H., /e$0 -., Mein (.A., et +l. A no@el prote$ti@e prion protein @+ri+nt t!+t
$olo$+li<e 4it! 0uru eLpoure. 5. :n'l. -. Me". 2009;%61:20562065. IPubMe"J
10. *!ibu2+ *., Hi'u$!i -., *!in 8.;., 1+tei!i -., 6it+moto 1. Prote$ti@e prion protein
pol2morp!im +'+int por+"i$ (reut<?el"t-+0ob "ie+e. 3+n$et. 1998;%51:>19.
IPubMe"J
11. *tep!enon #.A., (!iotti 6., :belin' (., Grot! #., #eArmon" *.-., Pruiner *./.,
(+rlon G.A. Ou+ntit+ti@e tr+it lo$i +??e$tin' prion in$ub+tion time in mi$e. Genomi$.
2000;69:>75%. IPubMe"J
12. 3lo2" *., En4u+<or E.5., /e$0 -., M+llinon G., P+rr+ll M., 1+r'on0i P., (ollin'e
-., Pi!er :. )"enti?i$+tion o? multiple Du+ntit+ti@e tr+it lo$i lin0e" to prion "ie+e
in$ub+tion perio" in mi$e. Pro$. 5+tl A$+". *$i. .*A. 2001;98:6279628%. IPM( ?ree
+rti$leJ IPubMe"J
1%. 3lo2" *., .p!ill -./., 1+r'on0i P.=., Pi!er :., (ollin'e -. )"enti?i$+tion o? 'eneti$
lo$i +??e$tin' moue7+"+pte" bo@ine pon'i?orm en$ep!+lop+t!2 in$ub+tion time in mi$e.
5euro'eneti$. 2002;>:7781. IPubMe"J
1>. Me+" *., Poulter M., .p!ill -., /e$0 -., ;!it?iel" -., ;ebb 1.:., (+mpbell 1.,
A"+mon G., #eri<ioti P., 1+bri<i *.-., et +l. Geneti$ ri0 ?+$tor ?or @+ri+nt (reut<?el"t
-+0ob "ie+e: + 'enome74i"e +o$i+tion tu"2. 3+n$et 5eurol. 2009;8:5766. IPM(
?ree +rti$leJ IPubMe"J
15. /e$0 -.A., (+mpbell 1., A"+mon G., Poulter M., .p!ill -., Molou :., (ollin'e -.,
Me+" *. Ao$i+tion o? + null +llele o? *P85 4it! @+ri+nt (reut<?el"t-+0ob "ie+e. -.
Me". Genet. 2008;>5:81%817. IPM( ?ree +rti$leJ IPubMe"J
16. 3lo2" *.:., M+2t!+m :.G., Pot+ H., Gri<en0o@+ -., Molou :., .p!ill -., Hummeri$!
H., ;!it?iel" -., Alper M.P., Me+" *., (ollin'e -. H:(1#2 i +o$i+te" 4it!
u$eptibilit2 to moue +n" !um+n prion "ie+e. P3o* Genet. 2009;5:e1000%8%. IPM(
17. Miller G. 5euro"e'ener+tion. (oul" t!e2 +ll be prion "ie+e\ *$ien$e.
2009;%26:1%%71%%9. IPubMe"J
18. Me2er73ue!m+nn M., (oom+r+4+m2 -., /olmont 1., 6+eer *., *$!+e?er (., 6il'er
:., 5euen$!4+n"er A., Abr+mo40i #., Pre2 P., -+ton A.3., et +l. :Lo'enou in"u$tion
o? $erebr+l bet+7+m2loi"o'enei i 'o@erne" b2 +'ent +n" !ot. *$ien$e.
2006;%1%:1781178>. IPubMe"J
19. H+rol" #., Abr+!+m 8., Hollin'4ort! P., *im 8., Gerri! A., H+m!ere M.3., P+!4+
-.*., Mo0@in+ =., #o4<ell 6., ;illi+m A., et +l. Genome74i"e +o$i+tion tu"2
i"enti?ie @+ri+nt +t (3. +n" P)(A3M +o$i+te" 4it! Al<!eimerX "ie+e. 5+t. Genet.
2009;>1:1088109%. IPM( ?ree +rti$leJ IPubMe"J
20. =+n #eerlin =.M., *leim+n P.M.A., M+rtine<73+'e M., (!en7Plot0in A., ;+n' 3.*.,
Gr+??78+"?or" 5.8., #i$0on #.;., 8+"em+0er 8., /oe@e /.P., Grom+n M., et +l.
(ommon @+ri+nt +t 7p21 +re +o$i+te" 4it! ?rontotempor+l lob+r "e'ener+tion 4it!
1#P>% in$luion. 5+t. Genet. 2010;>2:2%>2%9. IPM( ?ree +rti$leJ IPubMe"J
21. *imon7*+n$!e< -., *$!ulte (., /r+ -.M., *!+rm+ M., Gibb -.8., /er' #., P+i+n7
8ui< (., 3i$!tner P., *$!ol< *.;., Hern+n"e< #.G., et +l. Genome74i"e +o$i+tion tu"2
re@e+l 'eneti$ ri0 un"erl2in' P+r0inonX "ie+e. 5+t. Genet. 2009;>1:1%081%12.
IPM( ?ree +rti$leJ IPubMe"J
22. *!+tuno@ A., Mo0 6., 5e4!oue *., ;e+le M.:., *mit! /., =+n$e (., -o!non 3.,
=el"in0 -.H., @+n : M.A., @+n "en /er' 3.H., et +l. (!romoome 9p21 in por+"i$
+m2otrop!i$ l+ter+l $leroi in t!e .6 +n" e@en ot!er $ountrie: + 'enome74i"e
+o$i+tion tu"2. 3+n$et 5eurolo'2. 2010;9:98699>. IPM( ?ree +rti$leJ IPubMe"J
2%. 1!e ;ell$ome 1rut (+e (ontrol (onortium. Genome74i"e +o$i+tion tu"2 o?
1>,000 $+e o? e@en $ommon "ie+e +n" %,000 !+re" $ontrol. 5+ture.
2007;>>7:661678. IPM( ?ree +rti$leJ IPubMe"J
2>. Me+" *., ;!it?iel" -., Poulter M., *!+! P., .p!ill -., /e$0 -., (+mpbell 1., Al #uM+il2
H., Hummeri$! H., Alper M.P., (ollin'e -. Geneti$ u$eptibilit2, e@olution +n" t!e 0uru
epi"emi$. P!ilo. 1r+n. 8. *o$. 3on". / /iol. *$i. 2008;%6%:%7>1%7>6. IPM( ?ree
+rti$leJ IPubMe"J
25. Me+" *., Poulter M., /e$0 -., ;ebb 1., (+mpbell 1., 3ine!+n -., #ebrul+i M.,
-oiner *., ;+"4ort! -.#., 6in' A., et +l. )n!erite" prion "ie+e 4it! iL o$t+pepti"e
repe+t inertion+l mut+tionmole$ul+r +n+l2i o? p!enot2pi$ !etero'eneit2. /r+in.
2006;129:22972%17. IPubMe"J
26. ;ebb 1.:., Poulter M., /e$0 -., .p!ill -., A"+mon G., (+mpbell 1., 3ine!+n -.,
Po4ell (., /r+n"ner *., P+l *., et +l. P!enot2pi$ !etero'eneit2 +n" 'eneti$ mo"i?i$+tion
o? P1023 in!erite" prion "ie+e in +n intern+tion+l erie. /r+in. 2008;1%1:26%226>6.
27. ;ebb 1.:.P., ;!itt+0er -., (ollin'e -., Me+" *. A'e o? onet +n" "e+t! in in!erite"
prion "ie+e +re !erit+ble. Am. -. Me". Genet. / 5europ2$!i+tr. Genet.
2009;150/:>96501. IPubMe"J
28. Me+" *., M+!+l *.P., /e$0 -., (+mpbell 1., P+rr+ll M., Pi!er :., (ollin'e -. *por+"i$
]but not @+ri+nt](reut<?el"t-+0ob "ie+e i +o$i+te" 4it! pol2morp!im uptre+m
o? PRNP :Lon 1. Am. -. Hum. Genet. 2001;69:122512%5. IPM( ?ree +rti$leJ IPubMe"J
29. M$(orm+$0 -.:., /+2butt H.5., :@erin'ton #., ;ill 8.G., )roni"e -.;., M+non -.(.
P85P $ont+in bot! introni$ +n" uptre+m re'ul+tor2 re'ion t!+t m+2 in?luen$e
u$eptibilit2 to (reut<?el"t-+0ob "ie+e. Gene. 2002;288:1%91>6. IPubMe"J
%0. =ollmert (., ;in"l E., î+n' ;., 8oenber'er A., Aerr )., ;i$!m+nn H.:.,
/i$0eboller H., )lli' 1., 6ret<$!m+r H.A. *i'ni?i$+nt +o$i+tion o? + M129=
in"epen"ent pol2morp!im in t!e 5_ .18 o? t!e P85P 'ene 4it! por+"i$ (reut<?el"t
-+0ob "ie+e in + l+r'e Germ+n $+e7$ontrol tu"2. -. Me". Genet. 2006;>%:e5%. IPM(
%1. Hill A.P., -oiner *., ;+"4ort! -.#., *i"le 6.(., /ell -.:., /u"0+ H., )roni"e -.;.,
(ollin'e -. Mole$ul+r $l+i?i$+tion o? por+"i$ (reut<?el"t-+0ob "ie+e. /r+in.
200%;126:1%%%1%>6. IPubMe"J
%2. (ollin'e -., (l+r0e A. A 'ener+l mo"el o? prion tr+in +n" t!eir p+t!o'eni$it2.
*$ien$e. 2007;%18:9%09%6. IPubMe"J
%%. Gu"bM+rton #.P., ;+lter G./., 1!orlei?on G., *te?+non H., H+ll"oron /.=.,
Aum+no@i$! P., *ulem P., 1!orl+$iu *., G2l?+on A., *teinber' *., et +l. M+n2 eDuen$e
@+ri+nt +??e$tin' "i@erit2 o? +"ult !um+n !ei'!t. 5+t. Genet. 2008;>0:609615.
IPubMe"J
%>. ;ebb 1.:., P+l *., *i""iDue #., He+ne2 #.(., 3ine!+n -.M., ;+"4ort! -.#., -oiner
*., /e$0 -., ;roe *.-., *te@enon =., et +l. Pirt report o? (reut<?el"t-+0ob "ie+e
o$$urrin' in 2 iblin' uneLpl+ine" b2 P85P mut+tion. -. 5europ+t!ol. :Lp. 5eurol.
2008;67:8%88>1. IPubMe"J
%5. ;+r" H.-., :@erin'ton #., (ouen *.5., *mit!7/+t!'+te /., Gillie M., Murr+2 6.,
6ni'!t 8.*., *mit! P.G., ;ill 8.G. 8i0 ?+$tor ?or por+"i$ (reut<?el"t-+0ob "ie+e.
Ann. 5eurol. 2008;6%:%>7%5>. IPubMe"J
%6. #e@lin /., 8oe"er 6. Genomi$ $ontrol ?or +o$i+tion tu"ie. /iometri$.
1999;55:997100>. IPubMe"J
%7. Ho4ie /.5., #onnell2 P., M+r$!ini -. A ?leLible +n" +$$ur+te 'enot2pe imput+tion
met!o" ?or t!e neLt 'ener+tion o? 'enome74i"e +o$i+tion tu"ie. P3o* Genet.
2009;5:e1000529. IPM( ?ree +rti$leJ IPubMe"J
%8. M+r$!ini -., Ho4ie /., M2er *., M$=e+n G., #onnell2 P. A ne4 multipoint met!o"
?or 'enome74i"e +o$i+tion tu"ie b2 imput+tion o? 'enot2pe. 5+t. Genet.
2007;%9:90691%. IPubMe"J
%9. Pur$ell *., 5e+le /., 1o""7/ro4n 6., 1!om+ 3., Perreir+ M.A.8., /en"er #., M+ller
-., *0l+r P., "e /+00er P.).;., #+l2 M.-., *!+m P.(. P3)56: + tool et ?or 4!ole7'enome
+o$i+tion +n" popul+tion7b+e" lin0+'e +n+l2e. Am. -. Hum. Genet. 2007;81:559
575. IPM( ?ree +rti$leJ IPubMe"J
>0. G+o ^.Y., /e$0er 3.(., /e$0er #.M., *t+rmer -.#., Pro@in$e M.A. A@oi"in' t!e !i'!
/on?erroni pen+lt2 in 'enome74i"e +o$i+tion tu"ie. Genet. :pi"emiol. 2010;%>:100
Jurnal 6
/r+in. 2010 E$tober; 1%%(10): %0%0%0>2.
Publi!e" online 2010 *eptember 7. "oi: 10.109%&br+in&+4D2%>
PM()#: PM(29>7>29
Agent strain 7ariation in human prion
disease4 insights from a molecular and
pathological re7iew of the National
Institutes of +ealth series of
e8perimentally transmitted disease
Piero P+r$!i,
1
M+ur+ (e$+tti,
1
*il@io 5ot+ri,
1
;+lter -. *$!ul<7*$!+e??er,
2
*+bin+
(+pell+ri,
1
Armin Giee,
%
;en7Ou+n Aou,
>
H+n 6ret<$!m+r,
%
/ern+r"ino G!etti,
5
+n"
P+ul /ro4n
6
Go to:
Abstract
*iL $lini$o7p+t!olo'i$+l p!enot2pe o? por+"i$ (reut<?el"t-+0ob "ie+e !+@e been
$!+r+$teri<e" 4!i$! $orrel+te +t t!e mole$ul+r le@el 4it! t!e t2pe (1 or 2) o? t!e +bnorm+l
prion protein, PrP
1*:
, preent in t!e br+in +n" 4it! t!e 'enot2pe o? pol2morp!i$
(met!ionine or @+line) $o"on 129 o? t!e prion protein 'ene. Ho4e@er, to 4!+t eLtent
t!ee p!enot2pe 4it! t!eir $orrepon"in' mole$ul+r $ombin+tion (i.e. MM1, MM2,
==1 et$.) en$ip!er "itin$t prion tr+in upon tr+nmiion rem+in un$ert+in. ;e tu"ie"
t!e PrP
1*:
t2pe +n" t!e prion protein 'ene in +r$!i@+l br+in tiue ?rom t!e 5+tion+l
)ntitute o? He+lt! erie o? tr+nmitte" (reut<?el"t-+0ob "ie+e +n" 0uru $+e, +n"
$!+r+$teri<e" t!e mole$ul+r +n" p+t!olo'i$+l p!enot2pe in t!e +??e$te" non7!um+n
prim+te, in$lu"in' Duirrel, pi"er, $+pu$!in +n" A?ri$+n 'reen mon0e2. ;e ?oun" t!+t
t!e tr+nmiion propertie o? prion ?rom t!e $ommon por+"i$ (reut<?el"t-+0ob
"ie+e MM1 p!enot2pe +re !omo'eneou +n" i'ni?i$+ntl2 "i??er ?rom t!oe o? por+"i$
(reut<?el"t-+0ob "ie+e ==2 or M=2 prion. Anim+l inMe$te" 4it! i+tro'eni$
(reut<?el"t-+0ob "ie+e MM1 +n" 'eneti$ (reut<?el"t-+0ob "ie+e MM1 lin0e" to
t!e :2006 mut+tion !o4e" t!e +me p!enot2pi$ ?e+ture + t!oe in?e$te" 4it! por+"i$
(reut<?el"t-+0ob "ie+e MM1 prion, 4!ere+ 0uru mot $loel2 reemble" t!e
por+"i$ (reut<?el"t-+0ob "ie+e ==2 or M=2 prion i'n+ture +n" neurop+t!olo'2.
1!e ?in"in' in"i$+te t!+t t4o "itin$t prion tr+in +re lin0e" to t!e t!ree mot $ommon
(reut<?el"t-+0ob "ie+e $lini$o7p+t!olo'i$+l +n" mole$ul+r ubt2pe +n" 0uru, +n"
u''et t!+t 0uru m+2 !+@e ori'in+te" ?rom $+nnib+liti$ tr+nmiion o? + por+"i$
(reut<?el"t-+0ob "ie+e o? t!e ==2 or M=2 ubt2pe.
/eywords4 prion "ie+e, neurop+t!olo'2, neuro"e'ener+ti@e "ior"er, p!enot2pe,
tr+in t2pin'
Go to:
Introduction
1r+nmiible pon'i?orm en$ep!+lop+t!ie (1*:) or prion "ie+e +re in@+ri+bl2 ?+t+l
neuro"e'ener+ti@e "ior"er +??e$tin' !um+n +n" ot!er m+mm+l u$! + !eep, "eer,
el0 +n" $+ttle. )n !um+n, 1*: o$$ur 4orl"4i"e + por+"i$, 'eneti$ or +$Duire" "ie+e
+n" $omprie t!ree m+Mor "ie+e entitie 4it! @+ri+ble t!ou'! o@erl+ppin' p!enot2pe:
(reut<?el"t-+0ob "ie+e ((-#), Gertm+nn*trùler*$!ein0er 2n"rome +n" ?+t+l
inomni+. )n +""ition, t!e term )*r* !+ been +ttribute" to +n +$Duire" !um+n prion
"ie+e ?+llin' 4it!in t!e p!enot2pi$ pe$trum o? (-# t!+t +??e$te" prim+ril2 t!e Pore
lin'uiti$ 'roup o? t!e :+tern Hi'!l+n" o? P+pu+ 5e4 Guine+.
)n 1*:, +n +bnorm+l, bet+7!eet ri$! +n" p+rti+ll2 prote+e7reit+nt io?orm (PrP
1*:
) o?
t!e $ellul+r prion protein, PrP
(
, +$$umul+te in t!e ner@ou 2tem, +n" to + leer eLtent
in ot!er or'+n, +n" repreent t!e !+llm+r0 o? t!e "ie+e (/ro4n &$ '! ., 1986; 8obert &$
'! ., 1986). 1!e $on@erion o? PrP
(
to PrP
1*:
i + pot7tr+nl+tion+l e@ent, +n" in@ol@e +
$on?orm+tion+l $!+n'e o? t!e protein ((+u'!e2 &$ '! ., 1991; P+n &$ '! ., 199%) t!+t $+n be
tr+nmitte" b2 +n +uto$+t+l2ti$ me$!+nim (/ie$!0e &$ '! ., 200>). PrP
1*:
i t!ou'!t to be
+n eenti+l, i? not t!e eL$lui@e, $omponent o? t!e tr+nmiible +'ent, or prion
(Pruiner, 1998; ;eim+nn, 200>; A'u<<i &$ '! ., 2008).
Prion "ie+e $omprie + bro+" pe$trum o? $lini$o7p+t!olo'i$+l p!enot2pe t!+t !o4
!etero'eneit2 in "ie+e "ur+tion, 2mptom+tolo'2 +n" "itribution o? br+in leion u$!
+ pon'ioi, neuron+l lo +n" 'lioi, + 4ell + preen$e +n" morp!olo'2 o? +m2loi"
pl+Due (G+mbetti &$ '! ., 200%; G!etti &$ '! ., 200%; 6ret<$!m+r +n" P+r$!i, 2007).
#i??erent prion tr+in +re belie@e" to be t!e m+in $+ue o? 1*: p!enot2pi$ "i@erit2
(A'u<<i &$ '! ., 2007). 1*: tr+in 4ere ori'in+ll2 "e?ine" b2 t!eir "itin$t "ie+e
p!enot2pe upon tr+nmiion to 2n'eni$ +nim+l, 4!i$! perit on eri+l tr+nmiion
(Pr+er &$ '! ., 197%; /ru$e &$ '! ., 1991). ;it!in + 'i@en !ot pe$ie, prion tr+in "i??er
m+inl2 in t!eir in$ub+tion time, t!e "itribution o? $entr+l ner@ou 2tem @+$uol+tion
t!+t t!e2 pro"u$e +n" 4!et!er or not t!e2 in"u$e +m2loi" pl+Due. )n +""ition, t!e !ot
'enot2pe @+ri+bilit2 in t!e 'ene en$o"in' PrP
(
(PRNP), + "etermine" b2 pol2morp!im
or mut+tion, !+ +lo been re$o'ni<e" + + $+u+l ?+$tor ?or p!enot2pi$ !etero'eneit2
(/ru$e &$ '! ., 1991; P+lmer &$ '! ., 1991; Gol"?+rb &$ '! ., 1992; Gol"m+n &$ '! ., 199>;
/+rron &$ '! ., 2001; G+mbetti &$ '!+ , 200%; G!etti &$ '! ., 200%). #itin$t !um+n tr+in o?
t!e prion +'ent !+@e been "emontr+te" +?ter eLperiment+l tr+nmiion (1ellin' &$ '! .,
1996; /ru$e &$ '! ., 1997; Hill &$ '! ., 1997; 3+me<+ &$ '! ., 2001; 6ort! &$ '! ., 200%;
5onno &$ '! ., 2005; /i!op &$ '! ., 2006; 6ob+2+!i &$ '! ., 2010) but rem+in to be ?ull2
$!+r+$teri<e".
.n$ert+intie +lo rem+in re'+r"in' t!e mole$ul+r b+i o? 1*: tr+in +n" t!e
rel+tion!ip bet4een t!e +'ent tr+in +n" PrP (A'u<<i &$ '! ., 2007). #itin$t PrP
1*:

pro?ile or t2pe !+@e been ?oun" in bot! !um+n +n" +nim+l +n" $+n be "itin'ui!e"
b2 pe$i?i$ p!2i$o$!emi$+l propertie u$! + i<e +?ter prote+e tre+tment, "e'ree o?
prote+e reit+n$e, +n" $on?orm+tion+l t+bilit2 +n" 'l2$o?orm r+tio (6+$+0 &$ '!+ ,
1986; /een +n" M+r!, 199>; Mon+ri &$ '!+ , 199>; (ollin'e &$ '! ., 1996; P+r$!i &$ '!+ ,
1996, 1997, 2000; *omer@ille &$ '! ., 1997; *+?+r &$ '! ., 1998; 5ot+ri &$ '! ., 200>; /+ron &$
'! ., 2007; ;em!euer &$ '! ., 2009). 1!e "i??erent PrP
1*:
t2pe $+n be +o$i+te" 4it!
"itin$t "ie+e p!enot2pe e@en in ubMe$t 4it! t!e +me PRNP 'enot2pe (P+r$!i &$ '! .,
1999, 2000). Purt!ermore, it !+ been !o4n t!+t propertie o? t!e PrP
1*:
t2pe rel+te" to
protein $on?orm+tion, u$! + t!e i<e o? t!e prote+e7reit+nt $ore, +re o?ten m+int+ine"
+?ter inter7pe$ie tr+nmiion (1ellin' &$ '! , 1996), +lt!ou'! $!+n'e m+2 +lo o$$ur in
$ert+in re$ipient 'enot2pe (Hill &$ '! ., 1997; 6ob+2+!i &$ '! ., 2010). )n umm+r2,
$ir$umt+nti+l e@i"en$e u''et t!+t t!e tr+in p!enot2pe +re en$ip!ere" in "itin$t
terti+r2 or e@en Du+tern+r2 tru$ture o? PrP
1*:
, +lt!ou'! t!e ?orm+l proo? i till +bent.
Gi@en t!ee un$ert+intie +n" to +@oi" $on?uion, t!rou'!out t!i m+nu$ript t!e term
pr"on %$r'"n i ue" to re?er to t!e propert2 o? t!e prion +'ent to in"u$e + pe$i?i$ "ie+e
p!enot2pe in + 'i@en !ot 'enot2pe +?ter tr+nmiion, 4!ere+ t!e term PrP
1*:
t2pe
re?er to onl2 t!e bio$!emi$+l PrP
1*:
propertie, uu+ll2 "e?ine" b2 4etern blottin', t!+t
!+@e been +o$i+te" 4it! + 'i@en "ie+e p!enot2pe.
14o m+Mor !um+n PrP
1*:
t2pe +re 0no4n, 4!i$! !+@e been eLteni@el2 repro"u$e"
+mon' l+bor+torie: Wt2pe 1X 4it! + rel+ti@e mole$ul+r m+ o? t!e prote+e7reit+nt $ore
o? 21 0#+ +n" t!e prim+r2 $le+@+'e ite +t rei"ue 82, +n" Wt2pe 2X 4it! + rel+ti@e
mole$ul+r m+ o? 19 0#+ +n" t!e prim+r2 $le+@+'e ite +t rei"ue 97 (P+r$!i &$ '!+ , 1996,
1997, 2000).
PrP
1*:
t2pe 1 +n" 2, in $onMun$tion 4it! t!e 'enot2pe +t t!e met!ionine (M) & @+line (=)
PRNP $o"on 129, l+r'el2 $orrel+te 4it! p!enot2pi$ @+ri+bilit2 in !um+n por+"i$ 1*:
+n" pro@i"e + mole$ul+r b+i ?or "ie+e $l+i?i$+tion (i.e. MM1, MM2, ==1, et$.)
(P+r$!i &$ '! ., 1996, 1999). Purt!ermore, t!e +me !um+n PrP
1*:
t2pe "ete$te" in
por+"i$ 1*: 4ere +lo ?oun" to be +o$i+te" 4it! "itin$t p!enot2pe in i+tro'eni$
(-#, 0uru +n" ?+mili+l (-# (P+r$!i &$ '! ., 1997, 2000), t!u r+iin' t!e poibilit2 t!+t
t!e +me prion tr+in 4oul" be iol+te" upon tr+nmiion ?rom +ll t!ee 1*: ?orm,
in"epen"ent o? t!eir +pp+rentl2 "i??erent +etiolo'2.
1!e eLperiment+l tr+nmiion o? (-# +n" 0uru 4+ ?irt +$$ompli!e" in t!e 1960
t!rou'! t!e pioneerin' tu"ie o? G+M"ue0, Gibb +n" Alper +t t!e 5+tion+l )ntitute o?
He+lt! (5)H) (G+M"ue0 &$ '! ., 1966; Gibb &$ '! ., 1968). 1!i 'roun"7bre+0in' "i$o@er2
le" to +n inteni@e %072e+r ree+r$! pro'r+mme "urin' 4!i$! e@er+l !un"re" o? $+e
o? @+riou neurolo'i$+l "ior"er 4ere ino$ul+te" in non7!um+n prim+te. (lini$+l,
neurop+t!olo'i$+l +n" biolo'i$+l "+t+ $on$ernin' t!ee tr+nmiion !+@e been
publi!e" but !+@e not in$lu"e" tu"ie to i"enti?2 "itin$t p!enot2pe b2 me+n o? leion
pro?ilin' or mole$ul+r $!+r+$teri<+tion o? PrP
1*:
b2 4etern blottin', PrP
immuno!ito$!emitr2 +n" p+r+??in embe""e" tiue (P:1) blottin'. ;e +""re !ere t!e
iue o? prion tr+in @+ri+tion in !um+n 1*: +n" t!eir mole$ul+r b+i, 4it! +
2tem+ti$ re7+n+l2i o? "ie+e $!+r+$teriti$ in m+t$!e" !um+n +n" non7!um+n
prim+te tiue obt+ine" ?rom t!e 5)H erie o? tr+nmitte" $+e, 4!i$! pro@i"e +
!itori$+ll2 uniDue reour$e to tu"2 t!e iue o? !um+n prion tr+in in + $ompre!eni@e
erie o? tr+nmiion to prim+te.
Go to:
*aterials and methods
$ase and tissue selection
+uman cases
A tot+l o? 99 !um+n $+e 4ere ele$te" ?rom t!e 5)H "+t+b+e o? tr+nmitte" 1*:
b+e" on t!e +@+il+bilit2 o? ?ro<en tiue. )n +""ition, 1% tr+nmitte" 0uru $+e 4ere
ele$te" "epite t!e l+$0 o? ?ro<en tiue. A$$or"in' to t!e ori'in+l $lini$o7p+t!olo'i$+l
+n" 'eneti$ +n+l2e obt+ine" ?rom t!e 5)H "+t+b+e +n" pre@iou publi$+tion (/e$0 &$
'! ., 197%; *$rim'eour &$ '! ., 198%; /ro4n &$ '! ., 1986, 199>; Gol"?+rb &$ '! ., 1991;
(er@ena0o@a &$ '! ., 1998), t!e ele$te" $+e $onite" o? 90 por+"i$ (-#, 5 ?+mili+l
(-# $+rr2in' t!e :2006 mut+tion $ouple" 4it! met!ionine +t $o"on 129 in bot! mut+te"
+n" 4il"7t2pe +llele (:20067129MM), 2 i+tro'eni$ (-# reultin' ?rom $ont+min+te"
tereot+$ti$ intr+$erebr+l ::G nee"le (/ernoulli &$ '! ., 1977) +n" 15 0uru $+e. All
$+e !+" + neurop+t!olo'i$+ll2 @eri?ie" pon'i?orm en$ep!+lop+t!2, +n" in 99 $+e, t!e
"i+'noi 4+ $on?irme" b2 4etern blottin' (+ll but 1% 0uru $+e).
$linical analysis
(lini$+l "+t+ ?or t!e !um+n 1*: $+e 4ere +@+il+ble in +ll $+e, +n" to + l+r'e eLtent
in$lu"e" in + pre@iou publi$+tion (/ro4n &$ '! ., 199>).
)n$ub+tion time ?rom ino$ul+tion to t!e onet o? $lini$+l 2mptom +n" t!e "ur+tion o?
2mptom ?or t!e non7!um+n prim+te 4ere "r+4n ?rom 5)H $!+rt +n" pre@ioul2
publi!e" "+t+ (/ro4n &$ '! ., 199>). Por t!ee +n+l2e, 4e $oni"ere" +nim+l t!+t 4ere
ino$ul+te" intr+$erebr+ll2 4it! + 520U p!op!+te bu??ere" +line upenion o? ?re!7
?ro<en br+in tiue. ;e +pplie" t!i $riterion 4it! t!e +im to eL$lu"e t!e le+t number o?
+nim+l, in$e it 4+ pre@ioul2 ?oun" (/ro4n &$ '! ., 199>) in eri+l "ilution eLperiment
t!+t t!e len't! o? in$ub+tion time "oe not $!+n'e i'ni?i$+ntl2 in t!e 10 or 100 ?ol"
"ilution r+n'e, 4!ile it i i'ni?i$+ntl2 prolon'e" +t + 10
5
"ilution. Purt!ermore, it !oul"
be $oni"ere" t!+t mot o? t!e +nim+l in$lu"e" in t!e +n+l2e 4ere eLpoe" to + 10U
!omo'en+te, +n" t!e rel+ti@e proportion o? +nim+l inMe$te" 4it! + 5, 10 or 20U br+in
!omo'en+te +mon' t!e mot i'ni?i$+nt 'roup o? +nim+l 4+ @er2 imil+r (e.'. 5, 77
+n" 18U, repe$ti@el2, ?or t!e 'roup o? Duirrel mon0e2 inMe$te" 4it! por+"i$ (-#
MM1 +n" 17, 71 +n" 12U, repe$ti@el2, ?or t!e Duirrel mon0e2 inMe$te" 4it! por+"i$
(-# ==2).
/ei"e t!e $on$entr+tion, t!e @olume o? t!e ino$ul+te" !omo'en+te +lo @+rie", but t!i
m+inl2 +$$or"e" 4it! t!e i<e (pe$ie) o? prim+te: $!imp+n<ee (not in$lu"e" in t!e
preent tu"2), ?or eL+mple, routinel2 re$ei@e" 0.1 ml, 4!ere+ Duirrel mon0e2 uu+ll2
re$ei@e" 0.05 ml (P. /ro4n, peron+l $ommuni$+tion). E@er+ll, + tot+l o? 1%0
tr+nmiion eLperiment 4ere $oni"ere" ?or t!e $+l$ul+tion o? in$ub+tion time.
Primate brain tissues
A?ter $reenin' t!e 5)H +nim+l "+t+b+e, +ll poiti@e (i.e. neurop+t!olo'i$+ll2 @eri?ie"
pon'i?orm en$ep!+lop+t!2) +nim+l t!+t !+" been ino$ul+te" 4it! one o? t!e ele$te"
!um+n 1*: $+e, +n" ?or 4!i$! tiue (eit!er ?ro<en or ?iLe" or bot!) 4ere till
+@+il+ble, 4ere +mple". 1iue ?rom ?our "i??erent non7!um+n prim+te pe$ie (Duirrel,
$+pu$!in, pi"er +n" A?ri$+n 'reen mon0e2) 4+ obt+ine". 1o in$lu"e + m+n2 +nim+l
+ poible, +mplin' 4+ per?orme" irrepe$ti@e o? t!e +@+il+bilit2 o? t!e in?orm+tion on
in$ub+tion time. 1!e rel+tion!ip bet4een number o? !um+n $+e +n+l2e" +n" t!e
number o? +nim+l +@+il+ble ?or t!e +n+l2e o? in$ub+tion time, !itop+t!olo'i$+l
?e+ture +n" PrP
1*:
t2pin' ?or t!e mot i'ni?i$+nt 'roup (i.e. Duirrel mon0e2 +t ?irt
p++'e) i pro@i"e" in Pi'. 1A. 1!e l+r'e m+Morit2 o? tiue 4ere obt+ine" ?rom +nim+l
inMe$te" +t ?irt p++'e; !o4e@er, ?iLe" tiue 4+ +lo t+0en ?rom + 'roup o? Duirrel
mon0e2 t!+t 4ere inMe$te" eit!er +t e$on" p++'e or +?ter eri+l p++'e (Pi'. 1/).
Pi'ure 1
(A) 8el+tion!ip bet4een number o? +nim+l +@+il+ble ?or t!e +n+l2e o? in$ub+tion time
()5(./ 1)M:), !itop+t!olo'i$+l ?e+ture (PA1H), +n" PrP
1*:
t2pin' (PrP
1*:
) ?or t!e
l+r'et 'roup o? !um+n 1*: ubt2pe tr+nmitte" to Duirrel mon0e2 (?irt p++'e). )))
E@er+ll, ?ro<en tiue ?rom 100 prim+te 4+ +@+il+ble ?or PrP
1*:
t2pin' +n+l2e, +n"
?orm+lin ?iLe" tiue ?rom 9> +nim+l 4+ obt+ine" ?or neurop+t!olo'i$+l eL+min+tion.
Pro<en br+in tiue 4+ obt+ine" ?rom Duirrel (n F 72), $+pu$!in (n F 17), pi"er (n F 8)
+n" A?ri$+n 'reen (n F %) mon0e2. 3+r'e tiue blo$0 4ere +@+il+ble in mot $+e (i.e.
95U), 4!ere+ m+ll tiue ?r+'ment, uu+ll2 ?rom t!e $erebr+l $orteL, 4ere obt+ine"
?rom + ?e4 br+in. 1iue +mple ?or 4etern blot +n+l2e 4ere t+0en ?rom t!e $erebr+l
$orteL (uu+ll2 ?ront+l $orteL) in mot $+e; +mple ?rom t!e $erebellum +n" tri+tum
4ere +""ition+ll2 obt+ine" in iL pi"er mon0e2 br+in.
PiLe" br+in tiue 4+ obt+ine" ?rom Duirrel (n ,68, 50 +t ?irt p++'e +n" 18 +t e$on"
or eri+l p++'e), pi"er (n ,11), $+pu$!in (n ,10) +n" A?ri$+n 'reen (n ,5) mon0e2.
1!e tiue $onite" eit!er o? ?orm+lin ?iLe", p+r+??in embe""e" blo$0 or ?orm+lin ?iLe"
br+in li$e, or bot!. Por e+$! $+e, "epen"in' on +@+il+bilit2, e$tion 4ere obt+ine"
?rom + m+n2 + poible o? t!e ?ollo4in' br+in re'ion: ?ront+l, tempor+l, p+riet+l +n"
o$$ipit+l $orti$e, !ippo$+mpu, entor!in+l $orteL, tri+tum, t!+l+mu, !2pot!+l+mu,
mi"br+in +n" $erebellum.
Neuropathology
*emiDu+ntit+ti@e e@+lu+tion o? pon'i?orm $!+n'e 4+ $+rrie" out uin' !+em+toL2lin
+n" eoin t+ine" e$tion. :le@en br+in re'ion 4ere ele$te" ?or eL+min+tion (lite"
+bo@e). *pon'i?orm $!+n'e 4+ $ore" on + 0% $+le (not
"ete$t+ble&mil"&mo"er+te&e@ere) +n" leion pro?ile 4ere obt+ine". 1!e leion pro?ile i
+ 4ell7et+bli!e" emiDu+ntit+ti@e met!o" o? me+urin' t!e t+r'etin' o? pon'i?orm
$!+n'e to "i??erent br+in re'ion +n" reli+bl2 "i$rimin+te bet4een 1*: tr+in in mi$e
+n" ot!er pe$ie +n" bet4een por+"i$ (-# ubt2pe in !um+n (/ru$e &$ '! ., 1996,
1997; P+r$!i &$ '! ., 1999).
PrP immuno!ito$!emitr2 +n" P:1 blot 4ere per?orme" u$$e?ull2 onl2 on p+r+??in
embe""e" tiue blo$0 (t!e lon'7t+n"in' ?orm+lin7?iLe" tiue 2iel"e" ne'+ti@e reult,
preum+bl2 "ue to t!e @er2 lon' tor+'e in ?orm+lin). 1iue ?rom %0 Duirrel mon0e2
(2> +t ?irt p++'e +n" 6 +t e$on" or eri+l p++'e) 4+ eL+mine" 4it! t!ee t4o
te$!niDue. 1!e 2> +nim+l o? t!e ?irt 'roup 4ere inMe$te" 4it! !omo'en+te ?rom:
por+"i$ (-# MM1 (n ,6), por+"i$ (-# ==2 (n ,5), por+"i$ (-# MM 4it! + 20 0#+
PrP
*$
$ore (n , 1) (ee W8eultX e$tion), por+"i$ (-# M=2 4it! 0uru pl+Due (por+"i$
(-# M= 26) (n ,2), por+"i$ (-# M=1 (n ,2), 0uru (n ,%), i+tro'eni$ (-# MM1 (n
,2) +n" ?+mili+l (-# :2006129 M (n ,%). 1!e 6 +nim+l o? t!e e$on" 'roup 4ere
inMe$te" 4it! !omo'en+te ?rom por+"i$ (-# MM1 (n ,%) +n" 0uru (n ,%). *t+inin'
4+ obt+ine" in +ll e$tion t!+t 4ere +@+il+ble ?or t!e !itop+t!olo'i$+l +n+l2i. P+r+??in
e$tion ?rom ?orm+lin7?iLe" blo$0 4ere pro$ee" uin' t!e mono$lon+l +ntibo"ie %P>
4it! epitope +t PrP rei"ue 108111 +t 20 b'&ml $on$entr+tion (*i'net 3+b, MA, .*A)
+$$or"in' to pre@ioul2 publi!e" proto$ol (P+r$!i &$ '! ., 1996). PrP "epoit 4ere
$l+i?ie" +$$or"in' to t!eir morp!olo'2 (i.e. 2n+pti$, 'r+nul+r, ?o$+l pl+Due7li0e). P:1
blot 4+ per?orme" +$$or"in' to + pre@ioul2 "e$ribe" proto$ol (*$!ul<7*$!+e??er &$ '! .,
2000). :L+min+tion o? t!e t+inin' p+ttern ?or bot! PrP immuno!ito$!emitr2 +n" P:1
blot 4ere per?orme" blin" to t!e reult o? t!e mole$ul+r +n" !itop+t!olo'i$+l +n+l2i
+n" t!e t2pe o? !um+n ino$ulum.
Protein analysis
Prep+r+tion o? +mple in$lu"in' PrP
1*:
puri?i$+tion, 4etern blottin' +n" PrP
1*:
t2pin'
4ere per?orme" +$$or"in' to et+bli!e" met!o" (5ot+ri &$ '! ., 200>, 2007; P+r$!i &$ '! .,
2000, 2009 '). )n p+rti$ul+r, +ll +mple 4ere !omo'eni<e" in l2i bu??er plu I100
mmol&l 5+(l, 10 mmol&l :#1A, 0.5U (@&@) 5oni"et P >0, 0.5U (4&@) o"ium
"eoL2$!ol+te, 100 mmol&l 1riH(l, pH 6.9J +n" "i'ete" 4it! protein+e 6 (8o$!e
#i+'noti$, pe$i?i$ +$ti@it2 b2 $erti?i$+te o? +n+l2i: >7.9 .&m') +t + ?in+l
$on$entr+tion o? 5 .&ml. Puri?ie" PrP
1*:
4+ obt+ine" ?rom +bout >00 m' o? tiue ?rom
t!e $erebr+l $orteL, 4!i$! 4+ ubMe$te" to t!ree $2$le o? +r0o2l eLtr+$tion +n"
"i??erenti+l $entri?u'+tion to 2iel" t!e P% pellet. 8unnin' 'el 4it! "i??erent ep+r+tin'
"i$rimin+tor2 po4er (i.e. 5, 6.5 +n" 15 $m in len't!) 4ere ue". All +mple but t!oe
?rom $+pu$!in mon0e2 4ere probe" 4it! t!e mono$lon+l +ntibo"2 %P> (rei"ue 106
110, *i'net 3+b, MA, .*A) (6+$+0 &$ '! ., 1986; Aou &$ '! ., 2010), 4!ere+ $+pu$!in
mon0e2 !omo'en+te, 4!oe PrP i not re$o'ni<e" b2 %P>, 4ere probe" 4it! t!e
mono$lon+l +ntibo"2 9A2 (rei"ue 99101). 1!e immunore+$ti@it2 4+ @iu+li<e" b2
en!+n$e" $!emilumine$en$e (:(3 t+n"+r" or :(3 Plu, G: He+lt!$+re) on 6o"+0
/ioM+L 3i'!t ?ilm (:+tm+n 6o"+0 (o.) +n" 4it! 3A*7%000 $+mer+ (PuMi?ilm). 1o
Du+nti?2 t!e PrP
1*:
$ontent, 4e $omp+re" t!e i'n+l intenit2 b2 "enitometr2 (Ai"+
)m+'e An+l2<er @.>.15 o?t4+re, 8+2tet) 4it! + t+n"+r" $ur@e, obt+ine" b2 lo+"in' in
e+$! 'el + eri+l "ilution (n ,>) o? + por+"i$ (-# +mple $!oen + t+n"+r".
*olecular genetic analysis
All !um+n +mple 4ere re7+n+l2e", 4!ere+ t!e PRNP eDuen$e o? non7!um+n
prim+te 4+ obt+ine" ?rom pre@ioul2 publi!e" reult ((er@ena0o@a &$ '! ., 199>). )n
t!i re'+r" it i note4ort!2 t!+t +t @+ri+n$e 4it! !um+n, +ll non7!um+n prim+te pe$ie
$+rr2 met!ionine +t $o"on 129 ((er@ena0o@a &$ '! ., 199>). 1!e open re+"in' ?r+me o? t!e
PRNP 4+ +mpli?ie" + pre@ioul2 "e$ribe", uin' #5A puri?ie" ?rom br+in tiue
(P+r$!i &$ '! ., 1996). 1!e pol2mer+e $!+in re+$tion pro"u$t 4+ @iu+li<e" on + 1U
+'+roe 'el to "ete$t potenti+l inertion mut+tion or "eletion. Potenti+l point mut+tion
4ere initi+ll2 re@e+le" b2 +n+l2e b2 "en+turin' !i'!7per?orm+n$e liDui"
$!rom+to'r+p!2 +n" ubeDuentl2 $on?irme" b2 "ire$t eDuen$in' o? PRNP open re+"in'
?r+me. Pin+ll2, t!e $o"on 129 'enot2pe 4+ eL+mine" b2 "i'etion 4it! t!e retri$tion
en"onu$le+e 5p 1.
Go to:
esults
*olecular typing of human inocula
Mole$ul+r $l+i?i$+tion o? por+"i$, 'eneti$ +n" i+tro'eni$ (-# +n" o? t4o 0uru $+e
4+ per?orme" +$$or"in' to PrP
1*:
t2pe (P+r$!i &$ '! ., 1996, 1997, 1999) +n" PRNP
'enot2pe. )n +""ition, in?orm+tion re'+r"in' t!e $o"on 129 'enot2pe 4+ +@+il+ble ?or 6
out o? t!e 1% 0uru $+e l+$0in' ?ro<en m+teri+l. Amon' t!em, > 4ere ==, 1 M= +n" 1
MM. E@er+ll, t!e immunoblot +n+l2i o? PrP
1*:
?rom t!e !um+n +mple 4+ $onitent
4it! pre@ioul2 publi!e" "+t+. All but one +mple ?itte" 4it!in t!e pe$trum o? !um+n
PrP
1*:
pro?ile pre@ioul2 "e$ribe" in por+"i$ (-# (P+r$!i &$ '! ., 1996, 1997; 5ot+ri &$
'! ., 200>), $l+i$ i+tro'eni$ (-# 4it! MM 'enot2pe (P+r$!i &$ '! ., 1997), ?+mili+l (-#
(Mon+ri &$ '! ., 199>; P+r$!i &$ '! ., 2000) +n" 0uru (P+r$!i &$ '! ., 1997). )n p+rti$ul+r, t!e
t4o 0uru $+e 4it! ?ro<en tiue 4ere == +n" M= +t $o"on 129 +n" !o4e" PrP
1*:
t2pe
2, + 4e pre@ioul2 reporte" (P+r$!i &$ '! ., 1997), 4!ere+, + eLpe$te" ?rom pre@iou
reult (5ot+ri &$ '! ., 200>; P+r$!i &$ '! ., 2009 -), mot $+e belon'in' to t!e M= 26
por+"i$ (-# ubt2pe !o4e" + "uplet in$lu"in' + 20 0#+ b+n" in +""ition to t!e 19 0#+
?r+'ment (Pi'. 2). 1!e onl2 +t2pi$+l $+e 4+ MM +t $o"on 129 +n" !o4e" + protein+e
67reit+nt PrP
1*:
$ore o? +bout 20 0#+, 4!i$! mi'r+te" li'!tl2 ?+ter t!+n t2pi$+l t2pe 1
(Pi'. 2).
Pi'ure 2
;etern blot pro?ile o? PrP
1*:
eLtr+$te" ?rom !um+n br+in o? t!e 5)H erie o?
tr+nmitte" "ie+e (/ro4n &$ '! ., 199>). A $+e ?or e+$! o? t!e "i??erent mole$ul+r
ubt2pe t!+t 4ere ino$ul+te" in mon0e2 i !o4n (l+ne 16). 3+ne 2 !o4 t!e )))
1!e "emo'r+p!i$ +n" $l+i?i$+tion o? t!e "i??erent !um+n 1*: ub'roup, b+e" on t!e
mole$ul+r +n+l2e, +re !o4n in 1+ble 1. )n +""ition to t!e 0uru $+e, t!e erie
$omprie ot!er !itori$+ll2 rele@+nt $+e reporte" in t!e liter+ture be?ore t!e +"@ent o?
mole$ul+r biolo'2 +n" t!e "i$o@er2 o? PrP
1*:
+n" PRNP. 1!e2 in$lu"e one $+e
$l+i?ie" + +t+Li$ (-# b2 /ro4nell +n" Eppen!eimer (1965), t!e +t+Li$ (-# $+e
"e$ribe" b2 Gomori &$ '! . (197%) +n" t!e +t2pi$+l (-# $+e, 4it! 4i"epre+" 0uru
pl+Due, reporte" b2 *$!oene &$ '! . (1981). Mole$ul+r +n+l2e !o4e" t!+t bot! $+e
4it! t!e +t+Li$ por+"i$ (-# @+ri+nt 4ere ==2, 4!ere+ t!e $+e ?rom *$!oene &$ '! .
(1981) 4+ 'enot2pe" + MM +t $o"on 129 +n" $orrepon" to t!e +t2pi$+l $+e
"e$ribe" +bo@e 4it! t!e 20 0#+ PrP
1*:
b+n" (Pi'. 2). 1!i p+tient !+" 4or0e" + +
neurour'eon ?or m+n2 2e+r, 4!i$! r+ie t!e t!eoreti$+l poibilit2 t!+t !e !+" +n
i+tro'eni$ ?orm o? (-#, +lt!ou'! t!ere 4+ no re$or" o? !im p+rti$ip+tin' in +n oper+ti@e
pro$e"ure on + (-# p+tient (*$!oene &$ '! . 1981).
1+ble 1
#emo'r+p!i$ $!+r+$teriti$ +n" $l+i?i$+tion o? tr+nmitte" $+e
Incubation times
)n$ub+tion time in mon0e2 @+rie" i'ni?i$+ntl2 +mon' t!e "i??erent (-# ub'roup
(1+ble 2).
1+ble 2
)n$ub+tion time (in "+2) in "i??erent mon0e2 pe$ie
5ot+bl2, in$ub+tion time in bot! Duirrel +n" pi"er mon0e2 4ere !orter in +nim+l
ino$ul+te" 4it! tiue ?rom por+"i$ (-# MM1 t!+n in t!oe ino$ul+te" 4it! por+"i$
(-# ==2 or 0uru, +lt!ou'! t!i 4+ t+titi$+ll2 i'ni?i$+nt onl2 ?or t!e ==2 'roup in
Duirrel mon0e2 (1+ble 2). Purt!ermore, ?+mili+l (-# (:20067MM1) tr+nmitte" t!e
"ie+e to Duirrel mon0e2 4it! in$ub+tion time $omp+r+ble to por+"i$ (-# MM1.
Neuropathology and lesion profiles
Amon' t!e tri+" o? leion t!+t $!+r+$teri<e t!e neurop+t!olo'2 o? !um+n 1*: (i.e.
pon'i?orm $!+n'e, neuron+l lo +n" 'lioi), onl2 pon'i?orm $!+n'e 4+ prominent in
t!e non7!um+n prim+te. 5one o? t!e +nim+l !o4e" +m2loi" pl+Due.
&9uirrel monkeys
5europ+t!olo'i$+l eL+min+tion re@e+le" t!+t e+$! o? t!e eL+mine" +nim+l !+" ?e+ture
o?, +n" $oul" be e+il2 +i'ne" to, eit!er one o? t4o $le+rl2 "itin$t p+t!olo'i$+l
p!enot2pe (!en$e?ort! re?erre" to + A +n" /). 1!e !itop+t!olo'i$+l ?e+ture 4ere
!i'!l2 $onitent +mon' in"i@i"u+l +nim+l. P!enot2pe A +n" / !o4e" i'ni?i$+nt
"i??eren$e in t!e $!+r+$teriti$ o? t!e pon'i?orm $!+n'e, t!e leion pro?ile +n" t!e
p+ttern o? PrP "epoition (1+ble %). )n p!enot2pe A t!e pon'i?orm $!+n'e $onite" o?
rel+ti@el2 m+ll, "eli$+te @+$uole t!+t +??e$te" m+inl2 t!e $erebr+l $orteL, t!e $+u"+te
+n" put+men nu$lei +n" t!e t!+l+mu, 4!ere+ t!e !ippo$+mpu, t!e !2pot!+l+mu, t!e
br+intem +n" t!e $erebellum 4ere rel+ti@el2 p+re" (Pi' % +n" +n">). >). )n +""ition,
t!ere 4+ + "itin$ti@e, ?o$+l, l+min+r "itribution o? pon'i?orm $!+n'e in t!e ?i?t! l+2er
o? t!e o$$ipit+l $orteL (Pi'. %), 4!ere+ pon'i?orm $!+n'e +??e$te" +ll $orti$+l l+2er
4it! +n in$ont+nt pre"omin+nt in@ol@ement o? t!e "eep l+2er in t!e ot!er lobe ("+t+
not !o4n). Pin+ll2, PrP immuno!ito$!emitr2 +n" P:1 blottin' re@e+le" + "eli$+te
"i??ue 2n+pti$ p+ttern o? PrP
1*:
"epoition in +ll +re+ !o4in' pon'i?orm $!+n'e
(Pi' % +n" +n"5 5).
Pi'ure %
Hitop+t!olo'i$+l ?e+ture o? p!enot2pe A (A, $, %; +nim+l ino$ul+te" 4it! por+"i$ (-#
MM1) +n" p!enot2pe / ((, ", 3; +nim+l ino$ul+te" 4it! por+"i$ (-# ==2) in Duirrel
mon0e2. (A +n" $) *pon'i?orm $!+n'e $onitin' o? rel+ti@el2 m+ll "eli$+te @+$uole
)))
Pi'ure >
8e'ion+l pro?ile o? pon'i?orm $!+n'e in Duirrel mon0e2 ino$ul+te" 4it! "i??erent
(-# ubt2pe or 0uru. 14o "itin$t pro?ile $+n be i"enti?ie": in p!enot2pe A, +
i'ni?i$+nt pon'i?orm $!+n'e i een in onl2 t!e $erebr+l $orteL, tri+tum +n", to ome )))
Pi'ure 5
P:1 blot ?e+ture in Duirrel mon0e2 4it! p!enot2pe A (A) +n" / ((). (A) #i??ue
W2n+pti$X PrP t+inin' in t!e ?ront+l $orteL. (() (ombine" 2n+pti$ +n" ?o$+l, pl+Due7li0e
PrP immunore+$ti@it2 in t!e "eep l+2er o? t!e ?ront+l $orteL. )))
1+ble %
M+in ?e+ture o? p+t!olo'i$+l p!enot2pe A +n" / in mon0e2
)n $ontr+t to p!enot2pe A, pon'i?orm $!+n'e in p!enot2pe / $onite" o? l+r'er
@+$uole (Pi'. %), !o4e" + more $le+r7$ut l+min+r p+ttern in t!e "eeper l+2er o? t!e
$erebr+l $orteL, +n" +??e$te" pre"omin+ntl2 ub$orti$+l tru$ture r+t!er t!+n t!e $erebr+l
$orteL (Pi'. >, 1+ble %). )mmuno!ito$!emitr2 +n" P:1 blottin' re@e+le" ?o$+l,
rel+ti@el2 m+ll, pl+Due7li0e PrP "epoit in +""ition to t!e 2n+pti$ t+inin' (Pi' % +n"
+n"5 5).
1!e +n+l2i o? + 'roup o? 18 +nim+l in 4!i$! (-# or 0uru prion 4ere eri+ll2
tr+nmitte" (Pi'. 1/) eit!er in Duirrel mon0e2 (2 "+2 p++'e) or t!rou'! ot!er
prim+te pe$ie u$! + $!imp+n<ee or pi"er mon0e2 be?ore t!e re7inMe$tion in Duirrel
mon0e2 (eri+l p++'e) +lo !o4e" t4o "itin$t p!enot2pe $orrepon"in' to
p!enot2pe A +n" p!enot2pe / b+e" on !itop+t!olo'i$+l +n" immuno!ito$!emi$+l
eL+min+tion o? t!e $erebr+l $orteL, 4!i$! 4+ +@+il+ble ?or +ll $+e.
!ther primate species
Alt!ou'! t!e m+teri+l +@+il+ble 4+ not u??i$ient ?or + "et+ile" $omp+rion o? leion
pro?ile bet4een 'roup o? +nim+l re$ei@in' "i??erent ino$ul+, neurop+t!olo'i$+l
?e+ture o? t!e "ie+e in $+pu$!in, pi"er +n" A?ri$+n 'reen mon0e2 4ere $onitent
4it! t!oe ober@e" in Duirrel mon0e2.
)n p+rti$ul+r, t4o p!enot2pe repro"u$in' "itin$ti@e ?e+ture o? p!enot2pe A +n" / in
Duirrel, u$! + @+$uole i<e, intr+$orti$+l "itribution o? pon'i?orm $!+n'e +n" t!e
p+ttern o? PrP "epoition, 4ere een in bot! $+pu$!in +n" pi"er mon0e2, 4!ere+ in t!e
m+ll 'roup o? A?ri$+n 'reen mon0e2 eL+mine" (4!i$! 4ere +ll ino$ul+te" 4it!
por+"i$ (-# MM1), +ll +nim+l !o4e" ?e+ture $onitent 4it! p!enot2pe A.
(iochemical characteri-ation of PrP
T&%
in non-human primates
(omp+re" 4it! !um+n, t!e un'l2$o2l+te" prote+e7reit+nt $ore o? PrP
1*:
in mon0e2
+l4+2 mi'r+te" in t!e 2021 0#+ r+n'e +n" 4+ t!ere?ore ne@er $le+@e" $loe enou'! to
t!e (7terminu to re+$! t!e lo4er rel+ti@e mole$ul+r m+ (i.e. 19 0#+) o? !um+n PrP
1*:

t2pe 2. )n t!i re'+r" it i note4ort!2 t!+t, +t @+ri+n$e 4it! !um+n, +ll non7!um+n
prim+te pe$ie $+rr2 met!ionine +t $o"on 129 ((er@ena0o@a &$ '! ., 199>).
5e@ert!ele, t4o i'ni?i$+ntl2 "i??erent mi'r+tion PrP
1*:
$ore pro?ile (!en$e?ort!
re?erre" to + W+X +n" WbX) $oul" be "itin'ui!e" in bot! Duirrel (Pi'. 6) +n" $+pu$!in
mon0e2 (Pi'. 7), p+rti$ul+rl2 4!en lon' 'el 4it! in$re+e" reolution 4ere ue". 1!e
?irt (more $ommon) pro?ile !o4e" +n un'l2$o2l+te" ?r+'ment o? t!e +me i<e + t!e
!um+n PrP
1*:
t2pe 1, 4!ere+ t!e e$on" pro?ile in$lu"e" + ?+ter mi'r+tin' ?r+'ment o?
+bout 20 0#+ in +""ition to t!e 21 0#+ b+n" (Pi' 6 +n" +n"7). 7). Pro?ile W+X 4+ een in
bot! Duirrel +n" $+pu$!in mon0e2 4it! t!e p+t!olo'i$+l p!enot2pe A, 4!ile pro?ile WbX
4+ lin0e" to p!enot2pe / in t!ee t4o pe$ie. At @+ri+n$e 4it! Duirrel +n" $+pu$!in
mon0e2, t!e prote+e7reit+nt PrP
1*:
$ore ?rom pi"er mon0e2 !+" + mole$ul+r i<e o?
+bout 21 0#+ (pro?ile W+X) in +ll +nim+l +n+l2e", irrepe$ti@e o? 4!et!er t!e2 !+" +
p+t!olo'i$+l p!enot2pe A or /. Pin+ll2, PrP
1*:
eLtr+$te" ?rom A?ri$+n 'reen mon0e2,
4!i$! 4+ eL+mine" onl2 in $+e 4it! p!enot2pe A, +lo !o4e" + rel+ti@e mole$ul+r
m+ o? 21 0#+ $onitent 4it! pro?ile W+X.
Pi'ure 6
)mmunoblot +n+l2i o? prote+e7reit+nt PrP
1*:
eLtr+$te" ?rom br+in o? Duirrel
mon0e2 (l+ne %10) ino$ul+te" 4it! "i??erent (-# ubt2pe or 0uru. /r+in
!omo'en+te 4ere tre+te" 4it! protein+e 6 +n" probe" 4it! %P>. ApproLim+te
mole$ul+r )))
Pi'ure 7
)mmunoblot +n+l2i o? prote+e7reit+nt PrP
1*:
eLtr+$te" ?rom br+in o? $+pu$!in
mon0e2 (l+ne %10) ino$ul+te" 4it! "i??erent (-# ubt2pe or 0uru. /r+in
!omo'en+te 4ere tre+te" 4it! protein+e 6 +n" probe" 4it! mono$lon+l +ntibo"2 9A2.
ApproLim+te )))
)n +""ition to it i<e, t!e rel+ti@e +mount o? t!e t!ree m+Mor PrP
1*:
b+n" t!+t +re een
+?ter immunoblottin' (t!e o7$+lle" W'l2$o?orm r+tioX) o?ten $!+r+$teri<e 1*: ubt2pe
or prion tr+in. PrP
1*:
'l2$o?orm r+tio !o4e" + i'ni?i$+nt !etero'eneit2 in bot!
Duirrel +n" pi"er mon0e2. 14o PrP
1*:
pro?ile 4it! + t+titi$+ll2 i'ni?i$+nt "i??eren$e
in 'l2$o?orm r+tio 4ere ?oun" t!+t $orrel+te" 4it! p+t!olo'i$+l p!enot2pe A +n" /,
repe$ti@el2, in bot! Duirrel +n" pi"er mon0e2; in +""ition, in Duirrel mon0e2, t!e
t4o 'l2$op+ttern +lo m+t$!e" t!e t4o pro?ile W+X +n" WbX b+e" on PrP
1*:
i<e. 1!e
more $ommon pro?ile 4+ $!+r+$teri<e" b2 t!e "omin+n$e o? t!e "i'l2$o2l+te" ?r+'ment
o? PrP
1*:
(or b2 imil+r +mount o? mono'l2$o2l+te" +n" "i'l2$o2l+te" PrP
1*:
?orm in
pi"er), 4!ere+ t!e e$on" pro?ile !o4e" + l+r'er +mount o? t!e mono'l2$o2l+te"
?r+'ment (Pi'. 8). 1!e "i??eren$e bet4een t!e t4o PrP
1*:
'l2$o?orm p+ttern 4+
epe$i+ll2 pronoun$e" in pi"er mon0e2 (Pi'. 8/). Pin+ll2, in $+pu$!in mon0e2, t!e
'l2$o?orm r+tio o? PrP
1*:
"i" not !o4 + i'ni?i$+nt "i??eren$e bet4een t!e mi'r+tion
pro?ile W+X +n" WbX. Ho4e@er, +t @+ri+n$e 4it! Duirrel mon0e2, t!e number o? $+e
+n+l2e", epe$i+ll2 ?or pro?ile WbX, 4+ @er2 lo4.
Pi'ure 8
An+l2i o? PrP
1*:
'l2$o?orm r+tio in Duirrel (A) +n" pi"er (() mon0e2 ino$ul+te"
4it! "i??erent (-# ubt2pe or 0uru. 14o "itin$t PrP
1*:
'l2$op+ttern, W"X +n" WmX +re
!o4n. P+ttern W"X i $!+r+$teri<e" )))
;e !+@e $+l$ul+te" t!e tot+l +mount o? PrP
1*:
in e+$! br+in !omo'en+te obt+ine" ?rom
t!e Duirrel mon0e2 $erebr+l $orteL +n" ?oun" + i'ni?i$+nt @+ri+bilit2 +mon' t!e +??e$te"
+nim+l, 4it!out +n2 i'ni?i$+nt $orrel+tion 4it! t!e "ie+e p!enot2pe (Pi'. 9A). 1o
e+r$! ?or poible "i??eren$e in ot!er bio$!emi$+l propertie u$! + t!e olubilit2 in
"eter'ent, 4e !+@e +lo puri?ie" PrP
1*:
in + ele$te" 'roup o? Duirrel mon0e2 !o4in'
eit!er PrP
1*:
mi'r+tion pro?ile W+X (n ,8) or pro?ile WbX (n ,>) +n" e@+lu+te" t!e rel+ti@e
proportion o? PrP
1*:
in t!e "eter'ent7oluble (*%) +n" inoluble (P%) ?r+$tion. 1!e
+mount o? PrP
1*:
in t!e P% ?r+$tion 4+ @er2 imil+r bet4een t!e t4o 'roup, 4!ere+
Duirrel +??e$te" b2 p!enot2pe A !+" + i'ni?i$+ntl2 !i'!er +mount o? W"eter'ent olubleX
PrP
1*:
$omp+re" 4it! t!oe 4it! p!enot2pe / (Pi'. 9/).
Pi'ure 9
(A) Amount o? protein+e 67reit+nt PrP
1*:
in Duirrel mon0e2 tot+l br+in !omo'en+te.
1!e t4o 'roup o? +nim+l !o4in' t!e PrP
1*:
pro?ile W+X (n ,56) or WbX (n ,16) on
4etern blot +re )))
Pathological phenotypes: PrP
T&%
profiles and the type of human inocula
/ot! t!e p+t!olo'i$+l p!enot2pe +n" PrP
1*:
pro?ile (eit!er t!e ele$trop!oreti$ mobilit2 or
t!e 'l2$op+ttern or bot!) in t!e mon0e2 4ere i'ni?i$+ntl2 rel+te" to t!e t2pe o? ino$ul+.
1!e "+t+ 4ere l+r'el2 $onitent +$ro +ll mon0e2 pe$ie, +lt!ou'! t!e "+t+ ?rom
Duirrel mon0e2 4ere mu$! more in?orm+ti@e "ue to t!e !i'!er number o? +mple.
1!e "et+il $on$ernin' t!e $orrel+tion bet4een t2pe o? ino$ulum, p+t!olo'i$+l
p!enot2pe +n" PrP
1*:
pro?ile, + 4ell + t!e number o? +nim+l +n+l2e" ?or e+$! 'roup,
+re reporte" in 1+ble >. E@er+ll, +mple ?rom por+"i$ (-# MM1 +n" M=1, i+tro'eni$
(-# MM1, por+"i$ (-# MM1[2 +n" ?+mili+l (-# $+rr2in' t!e :2006 mut+tion
$ouple" 4it! met!ionine +t $o"on 129 pro"u$e" p!enot2pe A +n" PrP
1*:
pro?ile W+X,
4!ere+ t!e !omo'en+te ?rom por+"i$ (-# ==2, por+"i$ (-# M= 26 +n" ?rom t!e
0uru $+e pro"u$e" p!enot2pe / +n" PrP
1*:
pro?ile WbX. :L$eption to t!i rule 4ere
pi"er mon0e2, 4!i$! !o4e" + PrP
1*:
prote+e7reit+nt ?r+'ment $orrepon"in' to
pro?ile W+X in +ll +nim+l +n+l2e", irrepe$ti@e o? 4!et!er t!e2 !+" + p+t!olo'i$+l
p!enot2pe A or /. 5e@ert!ele, t!e $orrel+tion bet4een t!e PrP
1*:
'l2$op+ttern +n" t!e
p+t!olo'i$+l p!enot2pe A +n" / in pi"er mon0e2 4+ tri0in' (Pi'. 8, 1+ble >). A in
Duirrel mon0e2, t!e mot $ommon 'l2$o?orm pro?ile 4+ ober@e" in +nim+l 4it!
p+t!olo'i$+l p!enot2pe A, 4!ile t!e e$on" pro?ile, $!+r+$teri<e" b2 + "omin+nt
mono'l2$o2l+te" ?orm +n" + tri0in' un"er7repreent+tion o? t!e "i'l2$o2l+te" ?orm,
4+ lin0e" to p!enot2pe /.
1+ble >
P+t!olo'i$+l p!enot2pe (P+t!) +n" PrP
1*:
mi'r+tion p+ttern in "i??erent mon0e2 pe$ie
+$$or"in' to !um+n ino$ulum
Pin+ll2, + in'le por+"i$ (-# MM 2(, in 4!i$! onl2 PrP
1*:
t2pe 2 4+ "emontr+te" in
t4o +mple ?rom t!e $erebr+l $orteL +n" $erebellum, +lo !o4e" p!enot2pe A +n"
PrP
1*:
pro?ile W+X, 4!ere+ t!e +t2pi$+l MM $+e 4it! t!e 20 0#+ PrP
1*:
$ore !o4e"
p!enot2pe / +n" PrP
1*:
pro?ile WbX.
Go to:
"iscussion
)n t!e preent tu"2 4e !+@e $omp+re" t!e tr+nmiion propertie o? t!e mot $ommon
p!enot2pi$ ubt2pe o? por+"i$, ?+mili+l +n" i+tro'eni$ (-# + 4ell + 0uru in "i??erent
non7!um+n prim+te pe$ie. 1!i erie o? tr+nmitte" $+e i !itori$+ll2 uniDue, + it i
b+e" on t!e l+r'e 5)H tu"2 t!+t pro@i"e" t!e eenti+l e@i"en$e t!+t !um+n 1*: +re
tr+nmiible.
1!e tr+nmiion "+t+ in prim+te tron'l2 u''et t!+t t4o "itin$t prion tr+in +re
lin0e" to t!e t!ree mot $ommon por+"i$ (-# @+ri+nt, 4!i$! +$$ount ?or t!e 're+t
m+Morit2 o? !um+n prion "ie+e. More pe$i?i$+ll2, our reult !o4 t!+t t!e m2o$loni$
(-# p!enot2pe +o$i+te" 4it! PrP
1*:
t2pe 1 in $o"on 129 MM or M= PRNP 'enot2pe
(P+r$!i &$ '! ., 1999) i rel+te" to + prion tr+in t!+t i "itin$t ?rom t!+t +o$i+te" 4it!
t!e +t+Li$ +n" t!e 0uru7pl+Due p!enot2pe lin0e" to PrP
1*:
t2pe 2 +n" == or M=,
repe$ti@el2 (P+r$!i &$ '! ., 1999).
1!e reult o? t!i tu"2 +lo !o4 t!+t 0uru prion !+@e tr+nmiion propertie
eDui@+lent to por+"i$ (-# ==2 +n" M=2 4it! 0uru pl+Due (M= 26). 1!e ?in"in' i in
line 4it! pre@iou reult un"erl2in' t!e tri0in' imil+ritie in bot! $lini$o7p+t!olo'i$+l
?e+ture +n" PrP
1*:
propertie bet4een por+"i$ (-# ==2 or M= 26 +n" 0uru
(H+in?ellner &$ '! ., 1997; P+r$!i &$ '! ., 1997; M$3e+n &$ '! ., 1998; /r+n"ner &$ '! ., 2008;
M$3e+n, 2008). E@er+ll, t!e ?in"in' $on?irm t!e i"e+ t!+t 0uru ori'in+te" ?rom t!e
$!+n$e $onumption +n" $+nnib+liti$ "i??uion o? tiue ?rom +n in"i@i"u+l 4it!
por+"i$ (-#, +n" point to t!e prob+bilit2 o? eit!er + ==2 or +n M= 26 $+e, in$e 4e
"i" not ?in" e@i"en$e o? por+"i$ (-# MM1 prion in eLperiment+ll2 tr+nmitte" 0uru,
e@en in ubMe$t $+rr2in' t!e MM or M= 'enot2pe. )nteretin'l2, re$entl2 per?orme"
Wtr+$e b+$0X eLperiment !+@e in"i$+te" t!+t tr+nmiion o? por+"i$ (-# ==2 to + 129
MM in"i@i"u+l t!rou'! + "ur+ impl+nt 4+ +lo t!e me$!+nim 'ener+tin' t!e i+tro'eni$
(-# p!enot2pe +o$i+te" 4it! pl+Due, $+lle" p7"(-# (6ob+2+!i &$ '! ., 2010). 1!ee
?in"in' +re $onitent 4it! our ober@+tion in t!e 0uru $+e 4it! MM 'enot2pe +n" in
t!e +t2pi$+l MM $+e 4it! 0uru pl+Due +n" t!e PrP
1*:
20 0#+ b+n". 1!u, it +ppe+r t!+t
t!i prion tr+in, +lt!ou'! more ?reDuentl2 +o$i+te" 4it! t!e = $o"on 129 +llele, +lo
tr+nmit to in"i@i"u+l !omo<2'ou ?or t!e $o"on 129 met!ionine +llele, in 4!i$! it i
mole$ul+rl2 +n" p!enot2pi$+ll2 "itin'ui!+ble ?rom t!e mot $ommon MM&M=17
+o$i+te" tr+in. E? note, i+tro'eni$ (-# rel+te" to $ont+min+te" 'ro4t! !ormone
inMe$tion i +lo $!+r+$teri<e" b2 +m2loi" pl+Due "epoition o? 0uru t2pe +n" +lo +??e$t
t!e MM 'enot2pe in +""ition to 129 == +n" M= re$ipient (/illette "e =illemeur, 199>;
;ill, 200%; /ro4n, 2006).
1!e "i??erent tr+nmiion propertie o? por+"i$ (-# t2pe 1 ino$ul+ in MM or M=
$o"on 129 'enot2pe $omp+re" 4it! t!e t2pe 2 ino$ul+ in == or M= 'enot2pe +re +lo
$onitent 4it! "+t+ re$entl2 obt+ine" in tr+n'eni$ mi$e +n" "n ."$ro mo"el. 1!e tu"ie
$on"u$te" in tr+n'eni$ mi$e eLprein' eit!er !um+n MM, == or M= 'enot2pe +re o?
p+rti$ul+r interet ?or + $omp+rion 4it! our reult, +lt!ou'! mot o? t!em !+@e ?o$ue"
on @+ri+nt (-# +n", to + leer eLtent, on 'eneti$ 1*:, 4!ere+ t!e "+t+ $olle$te" t!u
?+r $on$ernin' t!e por+"i$ (-# ubt2pe +n" 0uru +re p+t$!2 +n" in$on$lui@e. *por+"i$
(-# prion tr+nmitte" to tr+n'eni$ mi$e 4it! eit!er MM or == 'enot2pe, 4it!
in$ub+tion time t!+t +re $onitent 4it! our $on$luion t!+t t!e MM1&M=1 +n"
==2&M= 26 por+"i$ (-# ubt2pe +re lin0e" to t4o "i??erent !um+n prion tr+in
(6ort! &$ '! ., 200%). *imil+r "+t+ on in$ub+tion time 4ere obt+ine" in +not!er tu"2
4!ere + ?e4 por+"i$ (-# ino$ul+ 4ere tr+nmitte" to tr+n'eni$ mi$e eLprein' !um+n
PrP 4it! M +t $o"on 129 to be $omp+re" 4it! t!e tr+nmiion propertie o? bo@ine
pon'i?orm en$ep!+lop+t!2 +n" @+ri+nt (-# prion (A+nte &$ '! ., 2002).
1!e inter+$tion bet4een !ot 'enot2pe o? t!e Wubtr+teX +n" t!e 'enot2pe +n" PrP
io?orm o? t!e prion Wee"X !+@e +lo been re$entl2 mo"elle" "n ."$ro uin' t!e protein
mi?ol"in' $2$li$+l +mpli?i$+tion (PM(A) te$!niDue. )t !+ been ?oun" t!+t ee" ?rom
M=1 +mpli?ie" e??i$ientl2 in MM (+n" to + leer "e'ree M=) ubtr+te +n" t!ere?ore
be!+@e imil+rl2 to MM1, 4!ere+ M=2, imil+rl2 to ==2, +mpli?ie" e??i$ientl2 in ==
ubtr+te (-one &$ '! ., 2008), 4!i$! i +lo $onitent 4it! t!e reult o? t!e preent
tu"2.
1!e tr+nmiion propertie o? 0uru +n" (-# iol+te !+@e +lo been $omp+re" in
tr+n'eni$ +n" 4il"7t2pe mi$e. ;+"4ort! &$ '! . (2008) in?erre" t!+t 0uru prion +re
"itin$t ?rom @+ri+nt (-# +n" !+@e tr+nmiion propertie eDui@+lent to t!oe o?
$l+i$+l (por+"i$) (-# prion, 4!ere+ M+nueli"i &$ '! . (2009) +r'ue" t!+t t!e 0uru
+'ent i + uniDue iol+te "itin$t ?rom (-#. .n?ortun+tel2, t!e ?+$t t!+t ;+"4ort! &$ '! .
(2008) ?+ile" to ?ull2 $!+r+$teri<e t!e !etero'eneit2 +o$i+te" 4it! por+"i$ (-# prion
+?ter tr+nmiion, +n" M+nueli"i &$ '! . (2009) "i" not mention 4!i$! iol+te o? por+"i$
(-# (i.e. mole$ul+r&p+t!olo'i$+l ubt2pe) 4+ ue" ?or tr+nmiion, limit t!e
interpret+tion o? t!eir reult +n" t!e $omp+rion 4it! t!e preent tu"2. 5e@ert!ele, 4e
4oul" +'ree 4it! t!e 'ener+l $on$luion o? ;+"4ort! &$ '! . (2008) but +lo !o4 t!+t
0uru prion "o not m+t$! t!e entire pe$trum o? por+"i$ (-#.
An in$re+in' bo"2 o? "+t+ in"i$+te t!e eLiten$e o? (-# $+e 4it! PrP
1*:
t2pe 1 +n" 2
$o7o$$urren$e in t!e +me br+in (P+r$!i &$ '! ., 1999; Puoti &$ '! ., 1999). ;e re$entl2
?oun" t!+t in por+"i$ (-# t!e $o7o$$urren$e o? PrP
1*:
t2pe 1 +n" 2 in@ol@e +bout %5U
o? por+"i$ (-# $+e +n" epe$i+ll2 +??e$t ubMe$t 4it! + $o"on 129 MM 'enot2pe
((+lc &$ '! ., 2009; P+r$!i &$ '! ., 2009 -). )n t!e preent erie o? tr+nmitte" $+e, t!e
per$ent+'e o? MM $+e 4it! t!e $o7o$$urren$e o? PrP
1*:
t2pe 1 +n" 2 4+ i'ni?i$+ntl2
lo4er, 4!i$! i $onitent 4it! t!e l+$0 o? u??i$ient tiue to per?orm re'ion+l +n+l2e.
5e@ert!ele, it i note4ort!2 t!+t +p+rt ?rom t!e +t2pi$+l MM $+e 4it! t!e 0uru pl+Due
+n" t!e 20 0#+ b+n" +n" t!e MM 0uru $+e, +ll MM $+e 4it! ?e+ture o? t!e MM 2(
por+"i$ (-# ubt2pe !o4e" i"enti$+l tr+nmiion propertie in"epen"ent o? t!e
preen$e o? PrP
1*:
t2pe 2 +n" it rel+ti@e +mount. 1!i +lo in$lu"e" one $+e in 4!i$!
4e 4ere +ble to "ete$t onl2 PrP
1*:
t2pe 2 in t!e t4o +mple t!+t 4ere +@+il+ble. 1!ere
+re t4o poible eLpl+n+tion ?or t!ee reult. Potenti+ll2, t!e prim+te pe$ie ue" 4ere
mu$! more u$eptible to MM1 t!+n MM 2( prion +n" t!i pre@ente" t!e +ppe+r+n$e o?
!itop+t!olo'i$+l ?e+ture rel+te" to MM 2( repli$+tion. Altern+ti@el2, t!e MM 2(
p!enot2pe in !um+n i not rel+te" to + pe$i?i$ prion tr+in but r+t!er to !ot 'enot2pi$
?+$tor t!+t +re reponible ?or t!e ($o7)+ppe+r+n$e o? t2pe 2 +n" t!e +o$i+te" MM 2(
p!enot2pe. Purt!er tr+nmiion tu"ie uin' +nim+l t!+t +re le permii@e to (-#
MM&M= 1 or (-# ==2 prion 4ill be nee"e" to "e?initi@el2 ol@e t!i iue.
1!e preent "+t+ +lo !+@e impli$+tion ?or t!e un"ert+n"in' o? ?+mili+l +n" +$Duire"
?orm o? prion "ie+e. ;e pre@ioul2 !o4e" t!+t t2pe 1 +n" t2pe 2 PrP
1*:
+re preent
in +ll ?orm o? (-# in"epen"ent o? t!e +pp+rent +etiolo'2 o? t!e "ie+e, i.e. por+"i$,
in!erite" or +$Duire" b2 in?e$tion (P+r$!i &$ '! ., 1997, 2000). 1!ee ober@+tion r+ie t!e
$riti$+l Duetion o? 4!et!er t!e +me b+i$ tr+in preent in por+"i$ (-# +re +lo
+o$i+te" 4it! t!e ?+mili+l ?orm o? t!e !um+n "ie+e +n", i? t!i i t!e $+e, 4!et!er
t!e uniDue p!enot2pi$ ?e+ture o? ome ?+mili+l prion "ie+e $+n be eLpl+ine" b2 +n
e??e$t o? t!e PRNP mut+tion t!+t i in"epen"ent ?rom t!e prion tr+in.
1!e preent "+t+ on t!e tr+nmiion o? i+tro'eni$ (-# +n" ?+mili+l (-# to prim+te
+lon' 4it! reult o? tr+nmiion eLperiment o? ?+mili+l (-# prion (:20067129 M +n"
)210=7129 M !+plot2pe) in b+n0 @ole (5onno &$ '! ., 2005) +n" ?+mili+l (-# (:20067
129 M +n" :20067129=) in tr+n'eni$ !um+ni<e" mi$e (A+nte &$ '! ., 2009) +re
$onitent 4it! t!i !2pot!ei. )nteretin'l2, in t!e l+tter tu"2 it 4+ ?oun" t!+t +t
@+ri+n$e 4it! t!e :20067129MM ino$ulum, t!e :20067129== ino$ulum tr+nmitte"
4it! + prolon'e" in$ub+tion time +n" t!e +??e$te" mi$e !o4e" pl+Due7li0e ?o$+l
"epoit, 4!i$! p+r+llel our ?in"in' 4it! por+"i$ (-# MM1 +n" ==2 prion in non7
!um+n prim+te.
Pre@iou tu"ie on por+"i$ (-# MM1, t!e mot $ommon por+"i$ !um+n (-# ubt2pe,
!+@e r+ie" t!e Duetion o? 4!et!er t!i rel+ti@el2 l+r'e 'roup o? $+e i !omo'eneou
+n" rel+te" to + in'le prion tr+in or r+t!er repreent + !etero'eneou 'roup in$lu"in'
t4o or more por+"i$ (-# ubt2pe. 1!e preent tu"2, b+e" on t!e l+r'et 'roup o?
tr+nmitte" por+"i$ (-# MM1 $+e to "+te, !o4e" !omo'eneou reult in term o?
in$ub+tion time, t2pe o? pon'i?orm $!+n'e, leion pro?ile +n" PrP
1*:
propertie. 1!e
$olle$ti@e reult, t!ere?ore, tron'l2 upport t!e i"e+ t!+t + in'le prion tr+in i
+o$i+te" 4it! por+"i$ (-# MM1, +n" +re in 0eepin' 4it! our ori'in+l $l+i?i$+tion, +t
@+ri+n$e 4it! ot!er $l+i?i$+tion 2tem t!+t $oni"ere" our MM1 $+e + +
!etero'eneou 'roup in$lu"in' t4o tr+in7rel+te" ubt2pe (A+nuo &$ '! ., 2001; Hill &$
'! ., 200%).
Por m+n2 2e+r it !+ been "eb+te" 4!et!er t!e tu"2 o? ?r+'ment i<e +n" 'l2$o?orm
r+tio o? PrP
1*:
pro@i"e u??i$ientl2 "itin$ti@e mole$ul+r m+r0er to +llo4 i"enti?i$+tion
o? prion tr+in. Eur "+t+ in"i$+te t!+t in !um+n, t!e PrP
1*:
pro?ile pro@i"e i'ni?i$+nt
in?orm+tion +bout t!e $+u+ti@e tr+in, +lt!ou'! it i not in"i$+ti@e o? it un"er +ll
$ir$umt+n$e in t!e +ben$e o? !itop+t!olo'i$+l "+t+. Por eL+mple, it i till "i??i$ult to
"itin'ui! bet4een $+e 4it! t!e +me PrP
1*:
t2pe (?or eL+mple, bet4een MM 21 +n"
MM 2() 4it!out 0no4in' t!e !itop+t!olo'i$+l "+t+. Purt!ermore, re$ent 4or0 ?rom our
'roup !+ !o4n t!+t in ome int+n$e t!e !itop+t!olo'i$+l eL+min+tion i e@en more
eniti@e t!+n t!e bio$!emi$+l PrP
1*:
t2pin' in t!e re$o'nition o? por+"i$ (-# $+e
4it! miLe" p!enot2pi$ ?e+ture (P+r$!i &$ '! ., 2009-).
(on$ernin' t!e @+lue o? PrP
1*:
t2pin' in t!e re$o'nition o? tr+in +??e$tin' "i??erent
pe$ie, it !+ been pre@ioul2 !o4n t!+t bot! PrP
1*:
i<e +n" 'l2$o?orm p+ttern m+2
$!+n'e +?ter inter7pe$ie tr+nmiion (Hill &$ '! ., 1997; 6ob+2+!i &$ '! ., 2010). )n
+'reement 4it! t!i @ie4, tr+nmiion o? por+"i$ (-# MM&M= 1 to non7!um+n
prim+te $onitentl2 repro"u$e" t!e i<e but not t!e 'l2$o?orm r+tio o? t!e ori'in+l t2pe.
:@en more tri0in'l2, tr+nmiion o? por+"i$ (-# ==2 or M= 26 "i" not repro"u$e
t!e i<e in bot! pi"er +n" Duirrel mon0e2, +n" t!e 'l2$o?orm r+tio in pi"er mon0e2.
)n t!i re'+r" it i note4ort!2 t!+t, +t @+ri+n$e 4it! por+"i$ (-# ==2 or M= 26
+??e$te" ubMe$t, bot! pi"er +n" Duirrel mon0e2 +re !omo<2'ou ?or met!ionine +t
$o"on 129 ((er@ena0o@a &$ '! ., 199>). 1!ere?ore, our "+t+ $on?irm t!+t PrP
1*:
t2pin'
pro@i"e + mole$ul+r i'n+ture ?or $ert+in prion tr+in 4it!in + $ert+in !ot 'enot2pe,
p+rti$ul+rl2 4!en $ombine" 4it! 'eneti$ +n" neurop+t!olo'i$+l "+t+, but i o? limite"
@+lue ?or tr+$in' t!eir p++'e +mon' "i??erent +nim+l pe$ie 4it!out tr+nmiion
eLperiment.
E@er+ll, t!e reult o? t!i tu"2, $ombine" 4it! t!oe obt+ine" b2 ot!er 'roup, in"i$+te
t!+t +t le+t ?our "itin$t tr+in o? prion +??e$t !um+n. A$$or"in' to t!eir rel+ti@e
?reDuen$2 in 4etern $ountrie t!e2 4oul" in$lu"e: (i) *tr+in A, rel+te" to t!e t2pi$+l (-#
p!enot2pe or m2o$loni$ @+ri+nt (PrP
1*:
t2pe 1 +n" +t le+t one M $o"on 129 +llele); (ii)
*tr+in /, rel+te" to t!e +t+Li$ +n" 0uru7pl+Due @+ri+nt o? (-# + 4ell + 0uru (PrP
1*:

t2pe 2 +n" +t le+t one = $o"on 129 +llele or PrP
1*:
o? 20 0#+ in $ombin+tion 4it! $o"on
129 MM); (iii) *tr+in (, rel+te" to @+ri+nt (-# (PrP
1*:
t2pe 2/ +n" +t le+t one M $o"on
129 +llele); +n" (i@) *tr+in #, rel+te" to ?+t+l inomni+, 4it! PrP
1*:
t2pe 2A (por+"i$
?orm) or 2/ (?+mili+l ?orm) +n" +t le+t one M $o"on 129 +llele.
;!et!er +""ition+l !um+n prion tr+in +re rel+te" to por+"i$ (-# MM 2(, por+"i$
(-# ==1, t!e re$entl2 i"enti?ie" +t2pi$+l por+"i$ 1*: $+e (G+mbetti &$ '!+ , 2008) or
ome r+re 'eneti$ ?orm o? + 2et untr+nmitte" prion "ie+e rem+in to be "etermine".
Go to:
3unding
8PE (8i$er$+ Pon"+ment+le Erient+t+) ?rom t!e .ni@erit2 o? /olo'n+ +n" t!e Gino
G+lletti Poun"+tion (to P.P.), 5+tion+l )ntitute o? He+lt! 'r+nt PH* AG0101%% +n" P01
AG1>%59.
Go to:
Acknowledgements
1!e +ut!or +re t!+n0?ul to #i+ne 6o?0e2, /+rb+r+ Poli$!i, 8oe 8i$!+r"on +n"
*+brin+ /onine'n+ ?or t!eir te$!ni$+l +it+n$e. 1!e +ut!or +re +lo 'r+te?ul to #r
Gi+nlui'i A+nuo ?or !i !elp in t!e $olle$tion o? tiue.
Go to:
Glossary
Abbre7iations
(-#
(reut<?el"t-+0ob "ie+e
5)H
5+tion+l )ntitute o? He+lt!
1*:
tr+nmiible pon'i?orm en$ep!+lop+t!ie
Go to:
eferences
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15. /ro4n P, (+t!+l+ P, (+t+i'ne P, G+M"ue0 #(. (reut<?el"t7-+0ob "ie+e:
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17. /ro4n P, Gibb (-, 8o"'er7-o!non P, A!er #M, *ulim+ MP, /+$ote A, et +l.
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20. /ru$e M:, M$(onnell ), Pr+er H, #i$0inon AG. 1!e "ie+e $!+r+$teriti$ o?
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21. /ru$e M:, ;ill 8G, )roni"e -;, M$(onnel ), #rummon" #, *uttie A, et +l.
1r+nmiion to mi$e in"i$+te t!+t Wne4 @+ri+ntX (-# i $+ue" b2 t!e /*:
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22. (+li ), (+tell+ni 8, Al!e0!lee A, (o!en Y, /le@in -, Yu+n -, et +l. (o7eLiten$e
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2%. (+u'!e2 /;, #on' A, /!+t 6*, :rnt #, H+2e *P, (+u'!e2 ;*. *e$on"+r2
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2>. (er@ena0o@a 3, /ro4n P, Gol"?+rb 3G, 5+'le -, Pettrone 6, 8ubentein 8, et +l.
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199>;25:1215962. IPM( ?ree +rti$leJ IPubMe"J
25. (er@ena0o@a 3, Gol"?+rb 3G, G+rruto 8, 3ee H*, G+M"ue0 #(, /ro4n P.
P!enot2pe7'enot2pe tu"ie in 0uru: impli$+tion ?or ne4 @+ri+nt (reut<?el"t7
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26. (ollin'e -, *i"le 6(, Me+" -, )roni"e -, Hill AP. Mole$ul+r +n+l2i o? prion
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27. Pr+er H, #i$0inon AG. *$r+pie in mi$e. A'ent7tr+in "i??eren$e in t!e
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28. G+M"ue0 #(, Gibb (-, Alper M. :Lperiment+l tr+nmiion o? + 0uru7li0e
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29. G+mbetti P, #on' A, Yu+n -, î+o ^, A!en' M, Al!e0!lee A, et +l. A no@el
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%0. G+mbetti P, 6on' O, Aou ;, P+r$!i P, (!en *G. *por+"i$ +n" ?+mili+l (-#:
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%1. G!etti /, 1+'li+@ini P, 1+0+o M, /u'i+ni E, Pi$$+r"o P. Here"it+r2 prion protein
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%2. Gibb (-, G+M"ue0 #(, A!er #M, Alper MP, /e$0 :, #+niel PM, et +l.
(reut<?el"t7-+0ob "ie+e (pon'i?orm en$ep!+lop+t!2): tr+nmiion to t!e
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%>. Gol"?+rb 3G, Peteren 8/, 1+b+ton M, /ro4n P, 3e/l+n$ A(, Mont+'n+ P, et +l.
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%5. Gol"m+nn ;, Hunter 5, *mit! G, Poter -, Hope -. PrP 'enot2pe +n" +'ent
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%6. Gomori A-, P+rtno4 M-, Horoupi+n #*, Hir+no A. 1!e +t+Li$ ?orm o?
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>9. Mon+ri 3, (!en *G, /ro4n P, P+r$!i P, Peteren 8/, Mi0ol -, et +l. P+t+l P+mili+l
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5>. P+n 6M, /+l"4in M, 5'u2en -, G+et M, *erb+n A, Grot! #, et +l. (on@erion
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57. P+r$!i P, Giee A, (+pell+ri *, /ro4n P, *$!ul<7*$!+e??er ;, ;in"l E, et +l.
(l+i?i$+tion o? por+"i$ (reut<?el"t7-+0ob "ie+e b+e" on mole$ul+r +n"
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58. P+r$!i P, 5ot+ri *, ;eber P, *$!immel H, /u"0+ H, Perrer ), et +l. )nter7
l+bor+tor2 +ement o? PrP
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t2pin' in (reut<?el"t7-+0ob "ie+e: + 4etern
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59. P+r$!i P, *tr+mmiello 8, 5ot+ri *, Giee A, 3+n'e@el" -, 3+"o'+n+ A, et +l.
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p!enot2pe +n" $o7o$$urren$e o? PrP
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60. P+r$!i P, Aou ;, ;+n' ;, /ro4n P, (+pell+ri *, G!etti /, et +l. Geneti$ in?luen$e
on t!e tru$tur+l @+ri+tion o? t!e +bnorm+l prion protein. Pro$ 5+tl A$+" *$i
.*A. 2000;97:1016872. IPM( ?ree +rti$leJ IPubMe"J
61. Pruiner */. Prion. Pro$ 5+tl A$+" *$i .*A. 1998;95:1%%6%8%. IPM( ?ree
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62. Puoti G, Gi+$$one G, 8oi G, (+n$i+ni /, /u'i+ni E, 1+'li+@ini P. *por+"i$
(reut<?el"t7-+0ob "ie+e: $o7o$$urren$e o? "i??erent t2pe o? PrP
1*:
in t!e +me
br+in. 5eurolo'2. 1999;5%:217%6. IPubMe"J
6%. 8obert G;, 3o?t!oue 8, /ro4n 8, (ro4 1-, /+rr2 8A, Pruiner */. Prion
protein immunore+$ti@it2 in !um+n tr+nmiible "ementi+. 5 :n'l - Me".
1986;%150:12%1%. IPubMe"J
6>. *+?+r -, ;ille H, )tri =, Grot! #, *erb+n H, 1or$!i+ M, et +l. :i'!t prion tr+in
!+@e PrP
1*:
mole$ule 4it! "i??erent $on?orm+tion. 5+t Me". 1998;>:115765.
IPubMe"J
65. *$!oene ;(, M+ter (3, Gibb (-, G+M"ue0 #(, 12ler H8, Moore P#, et +l.
1r+nmiible pon'i?orm en$ep!+lop+t!2 ((reut<?el"t7-+0ob "ie+e). At2pi$+l
$lini$+l +n" p+t!olo'i$+l ?in"in'. Ar$! 5eurol. 1981;%8:>7%7. IPubMe"J
66. *$!ul<7*$!+e??er ;-, 1$!f0e *, 6r+ne?u 5, #rfe ;, H+ue78eitner #, Giee
A, et +l. 1!e p+r+??in7embe""e" tiue blot "ete$t PrP
1*:
e+rl2 in t!e in$ub+tion
time in prion "ie+e. Am - P+t!ol. 2000;156:516. IPM( ?ree +rti$leJ IPubMe"J
67. *$rim'eour :M, M+ter (3, Alper MP, 6+@en -, G+M"ue0 #(. A $lini$o7
p+t!olo'i$+l tu"2 o? + $+e o? 0uru. - 5eurol *$i. 198%;59:26575. IPubMe"J
68. *omer@ille 8A, (!on' A, MulDueen E., /ir0ett (8, ;oo" *(, Hope -.
/io$!emi$+l t2pin' o? $r+pie tr+in. 5+ture. 1997;%86:56>. IPubMe"J
69. 1ellin' G(, P+r$!i P, #eArmon" *-, (ortelli P, Mont+'n+ P, G+bi<on 8, et +l.
:@i"en$e ?or t!e $on?orm+tion o? t!e p+t!olo'i$ io?orm o? t!e prion protein
en$ip!erin' +n" prop+'+tin' prion "i@erit2. *$ien$e. 1996;27>:207982.
IPubMe"J
70. ;+"4ort! -#, -oiner *, 3ine!+n -M, #ebrul+i M, PoL 6, (ooper *, et +l.
6uru prion +n" por+"i$ (reut<?el"t7-+0ob "ie+e prion !+@e eDui@+lent
tr+nmiion propertie in tr+n'eni$ +n" 4il"7t2pe mi$e. Pro$ 5+tl A$+" *$i
.*A. 2008;105:%88590. IPM( ?ree +rti$leJ IPubMe"J
71. ;em!euer ;M, /enet+" *3, ;re"e A, *$!ul<e7*turm ., ;em!euer ;:,
H+!m+nn ., et +l. *imil+ritie bet4een ?orm o? !eep $r+pie +n" (reut<?el"t7
-+0ob #ie+e +re en$o"e" b2 "itin$t prion t2pe. Am - P+t!ol. 2009;175:2566
7%. IPM( ?ree +rti$leJ IPubMe"J
72. ;eim+nn (. 1!e t+te o? t!e prion. 5+t 8e@ Mi$robiol. 200>;2:86171.
IPubMe"J
7%. ;ill 8G. A$Duire" prion "ie+e: i+tro'eni$ (-#, @+ri+nt (-#, 0uru. /r Me"
/ull. 200%;66:25565. IPubMe"J
7>. A+nuo G, P+rin+<<o A, Piorini M, Gel+ti M, (+t+'n+ A, 8i'!etti PG, et +l. pH7
"epen"ent prion protein $on?orm+tion in $l+i$+l (reut<?el"t7-+0ob "ie+e. -
/iol (!em. 2001;276:>0%7780. IPubMe"J
75. Aou ;O, 3+n'e@el" -, î+o ^, (!en *, M$Geer P3, Yu+n -, et +l. PrP
$on?orm+tion+l tr+nition +lter pe$ie7pre?eren$e o? + PrP pe$i?i$ +ntibo"2. -
/iol (!em. 2010;285:1%87>8>. IPM( ?ree +rti$leJ IPubMe"J
Jurnal ;
=irol -. 2011; 8: 559.
Publi!e" online 2011 #e$ember 2>. "oi: 10.1186&17>%7>22^787559
PM()#: PM(%296552
An o7er7iew of human prion diseases
Mu!+mm+" )mr+n
1
+n" *+Dib M+!moo"
2
Go to:
Abstract
Prion "ie+e +re tr+nmiible, pro'rei@e +n" in@+ri+bl2 ?+t+l neuro"e'ener+ti@e
$on"ition +o$i+te" 4it! mi?ol"in' +n" +''re'+tion o? + !ot7en$o"e" $ellul+r prion
protein, PrP
(
. 1!e2 !+@e o$$urre" in + 4i"e r+n'e o? m+mm+li+n pe$ie in$lu"in'
!um+n. Hum+n prion "ie+e $+n +rie por+"i$+ll2, be !ere"it+r2 or be +$Duire".
*por+"i$ !um+n prion "ie+e in$lu"e (ruet<?el"t7-+$ob "ie+e ((-#), ?+t+l inomni+
+n" @+ri+bl2 prote+e7eniti@e prionop+t!2. Geneti$ or ?+mili+l prion "ie+e +re $+ue"
b2 +utoom+l "omin+ntl2 in!erite" mut+tion in t!e 'ene en$o"in' ?or PrP
(
+n" in$lu"e
?+mili+l or 'eneti$ (-#, ?+t+l ?+mili+l inomni+ +n" Gertm+nn7*trùler7*$!ein0er
2n"rome. A$Duire" !um+n prion "ie+e +$$ount ?or onl2 5U o? $+e o? !um+n prion
"ie+e. 1!e2 in$lu"e 0uru, i+tro'eni$ (-# +n" + ne4 @+ri+nt ?orm o? (-# t!+t 4+
tr+nmitte" to !um+n ?rom +??e$te" $+ttle @i+ me+t $onumption epe$i+ll2 br+in. 1!i
re@ie4 preent in?orm+tion on t!e epi"emiolo'2, etiolo'2, $lini$+l +ement,
neurop+t!olo'2 +n" publi$ !e+lt! $on$ern o? !um+n prion "ie+e. 1!e role o? t!e PrP
en$o"in' 'ene (PRNP) in $on?errin' u$eptibilit2 to !um+n prion "ie+e i +lo
"i$ue".
/eywords4 Prion, Prion "ie+e, PRNP, 1*:, (-#
Go to:
(ackground
Prion "ie+e +re tr+nmiible protein mi?ol"in' "ior"er in 4!i$! mi?ol"in' o? +
!ot7en$o"e" prion protein (PrP) o$$ur. PrP i + 25% +mino +$i" (++) protein. 1!e ?irt
22 57termin+l ++ +re remo@e" ?rom PrP +?ter it tr+nport to en"opl+mi$ reti$ulum,
4!ile t!e l+t 2% (7termin+l ++ +re $le+@e" o?? +?ter t!e +""ition o?
'l2$o2lp!op!+ti"2linoitol (GP)) +n$!or, 4!i$! !elp t!e protein to +tt+$! to t!e outer
ur?+$e o? $ell membr+ne. PrP m+2 eLit in t4o ?orm: + norm+l $ellul+r prion protein
"ei'n+te" + PrP
(
+n" + p+t!o'eni$ mi?ol"e" $on?ormer "ei'n+te" + PrP
*$
. /ot! PrP
(
+n" PrP
*$
$on?ormer +re en$o"e" ?rom t!e +me eDuen$e o? t!e 16 0b in'le $op2
PRNP 'ene t!+t i poitione" on t!e !ort (p) +rm o? !um+n $!romoome 20 (20p1%),
?rom b+e p+ir >,666,7967>,682,2%%. 1!e !um+n PRNP $ont+in t4o eLon 4it! t!e
e$on" one $+rr2in' t!e 4!ole open re+"in' ?r+me. 1!e +bnorm+l PrP
*$
io?orm "i??er
?rom t!e norm+l PrP
(
io?orm in e$on"+r2 +n" terti+r2 tru$ture, but not in prim+r2
+mino +$i" eDuen$e. PrP
(
i pre"omin+ntl2 ri$! in +lp!+ !eli$+l $ontent, 4!ile PrP
*$
i
pre"omin+ntl2 ri$! in bet+ !eet $ontent I175J. 1!i $on?orm+tion+l "i$rep+n$2 ren"er
t!e PrP
*$
io?orm eLtremel2 reit+nt to proteol2i +n" "e'r+"+tion b2 $on@ention+l
me+n o? $!emi$+l +n" p!2i$+l "e$ont+min+tion or "iin?e$tion. )n $ontr+t to PrP
*$
,
PrP
(
i oluble in non7"en+turin' "eter'ent +n" i $ompletel2 "e'r+"e" b2 prote+e
I1,%J.
1!e uper$ript (*$) !+ been ue" to re?er to $r+pie, t!e ?irt +n" t!e mot +n$ient
+nim+l 1r+nmiible *pon'i?orm :n$ep!+lop+t!2 (1*:). M+n2 +ut!or +lo ue
uper$ript ot!er t!+n (*$) to "itin'ui! norm+l +n" p+t!o'eni$ ("ie+e7$+uin')
io?orm. 1!ee in$lu"e (re) ?or reit+nt +n" (#i) ?or "ie+e. An +bbre@i+te" n+me o? +
prion "ie+e $+n +lo be ue" + uper$ript to point out t!e ori'in o? t!e p+t!o'eni$
io?orm i.e. PrP
*$
or PrP
(-#
. 1!e p+t!o'eni$ $on?ormer +re impl2 $+lle" prion (t!e
in?e$tiou protein p+rti$le) I%J.
A$$or"in' to ee"in'7nu$le+tion mo"el, t!e preeLitin' or +$Duire" PrP
*$
oli'omer
$+t+l2<e t!e $on@erion o? PrP
(
mole$ule into PrP
*$
?ibril t!e bre+0+'e o? 4!i$!
pro@i"e more PrP
*$
templ+te ?or t!e $on@erion pro$e. 1!e pro$e o? prion
prop+'+tion in t!e br+in reult in t!e p+t!o'enei o? prion "ie+e I6J. *iLteen "i??erent
@+ri+nt o? prion "ie+e !+@e been reporte" o ?+r: nine in !um+n +n" e@en in +nim+l.
1!e etiolo'2, !ot r+n'e +n" 2e+r o? "e$ription ?or t!ee "ie+e @+ri+nt +re 'i@en in
1+ble 1+ble1. 1. )n t!e preent re@ie4, + brie? "e$ription o? !um+n prion "ie+e i
pro@i"e".
1+ble 1
:tiolo'2 o? prion "ie+e
&poradic $ruet-feldt-Jacob disease <s$J"=
*por+"i$ (ruet<?el"t7-+$ob "ie+e +$$ount ?or 85U o? +ll (-# $+e 4it! +nnu+l
4orl"4i"e in$i"en$e o? 172 $+e&million popul+tion I27J. )t o$$ur eDu+ll2 in bot! eLe
4it! + pe+0 +'e o? onet bet4een 55 +n" 75 2e+r. *ome 2oun'er (belo4 20 2e+r) +n"
ol"et (+bo@e 90 2e+r) $+e !+@e +lo been reporte". (lini$+l 2mptom in$lu"e r+pi"l2
pro'rei@e "ementi+, $erebell+r "2?un$tion in$lu"in' mu$le in$oor"in+tion, +n" @iu+l,
pee$! +n" '+it +bnorm+litie. #ementi+ i t!e m+Mor 2mptom ?ollo4e" b2 pont+neou
or in"u$e" m2o$loni+. #urin' t!e "ie+e $oure, 2mptom o? p2r+mi"+l +n"
eLtr+p2r+mi"+l "2?un$tion 4it! re?leLe, tremor, p+ti$it2 +n" ri'i"it2, +n" be!+@ior+l
$!+n'e 4it! +'it+tion, $on?uion +n" "epreion m+2 +lo be ober@e". At t!e en" o? t!e
"ie+e $oure, mot o? p+tient 'o into + t+te o? +0ineti$ mutim (t!e2 be$ome
unreponi@e to eLterior timuli) I28,29J.
1!e preen$e o? pon'i?orm $!+n'e +n" p+re PrP
*$
"itribution in (5* o? (-#
p+tient +re t!e !+llm+r0 o? neurop+t!olo'2 o? t!e "ie+e. 1!e "epoit o? +m2loi"
pl+Due m+2 +lo be noti$e" in 5710U o? $+e I28,%0J. En t!e b+i o?
$lini$op+t!olo'i$+l ?in"in', "i??erent @+ri+nt o? (-# !+@e been "e$ribe". Am+uroti$
or Hein"en!+in @+ri+nt i $!+r+$teri<e" b2 r+pi"l2 pro'rei@e "ementi+, m2o$lonu,
@iu+l "iturb+n$e u$! + !+llu$in+tion, @iu+l +'noi+ +n" $orti$+l blin"ne, +n"
!ort "ie+e "ur+tion; /ro4nell +n" Eppen!eimer @+ri+nt i $!+r+$teri<e" b2 +n e+rl2
+n" pre"omin+nt $erebell+r +t+Li+ +n" rel+ti@el2 l+te "ementi+; t!e t!+l+mi$ ?orm i
$!+r+$teri<e" b2 "ementi+ +n" mo@ement "ior"er; 4!ile t!e p+nen$ep!+li$ -+p+nee
@+ri+nt i $!+r+$teri<e" b2 !i'! +mount o? $ell in (*P, pro?oun" "+m+'e o? t!e 4!ite
m+tter +n" + @er2 lo4 "ie+e $oure I28,29,%1,%2J.
En t!e b+i o? $lini$+l, biolo'i$+l, ele$trop!2iolo'i$+l +n" neurop+t!olo'i$+l ?in"in',
(-# $+e $+n be $l+i?ie" + poible, prob+ble or "e?inite $+e. Poible $+e +re
$!+r+$teri<e" b2 r+pi"l2 pro'rei@e "ementi+ +$$omp+nie" b2 +t le+t t4o o? t!e
?ollo4in' 2mptom: m2o$lonu, $erebell+r or @iu+l 2mptom, p2r+mi"+l or
eLtr+p2r+mi"+l i'n, +0ineti$ mutim +n" "ie+e $oure o? le t!+n 2 2e+r. Poible
$+e +re $oni"ere" prob+ble $+e 4!en t!e2 re@e+l + $!+r+$teriti$ perio"i$ ::G or
in$re+e" le@el o? 1>7%7% protein in (*P I29J. #e?inite $+e +re "e?ine" b2 t!e preen$e
o? pon'i?orm $!+n'e or PrP
*$
re+$ti@it2 in br+in. 5ot+bl2, (-# 2mptom m+2 +lo be
een in "ior"er li0e Al<!eimerN "ie+e, "i??ue 3e42 bo"2 "ie+e or ?ront+l "ementi+,
p+r+neopl+ti$ 2n"rome, tumor or tro0e +n" in "ior"er 4it! toLi$, nutrition,
met+bolim or in?e$tion7rel+te" $+ue. #i??erenti+l "i+'noi ?or poible +n" prob+ble
$+e o? (-# i, t!ere?ore, nee"e". (ompute" tomo'r+p!2 ((1) m+2 re@e+l i'n+l o?
mil" br+in +trop!2 in ome $+e. 1!e ue o? $r+ni+l m+'neti$ reon+n$e im+'in' (M8))
i !elp?ul in "ete$tin' br+in +trop!2 +n", in more t!+n 50U o? $+e, m+2 re@e+l !i'!
i'n+l on 12, ?l+ir or "i??uion74ei'!te" eDuen$e in b++l '+n'li+ or in $erebr+l or
$erebell+r $orteL I29J. Almot +ll (-# $+e !o4 +ltere" ele$troen$ep!+lo'r+p!i$
(::G) i'n+l. *lo4 4+@e +$ti@it2 rem+in $ont+nt +n" "eterior+te 4it! t!e pro'reion
o? t!e "ie+e. Peu"o7perio"i$ !+rp 4+@e $ompleLe o? 1 Hert< +re $!+r+$teriti$ o?
::G in (-# $+e. 1o o@er$ome t!e tr+nient n+ture o? perio"i$ !+rp 4+@e $ompleLe,
repe+te" ::G re$or"in' +re reDuire" I29,%%J.
1!e $lini$op+t!olo'i$+l +n" mole$ul+r p!enot2pe o? (-# +re 're+tl2 in?luen$e" b2
@+ri+tion in PRNP. PRNP pol2morp!im in re'ul+tor2 + 4ell + $o"in' eDuen$e
!+@e been +o$i+te" 4it! pre"ipoition to t!e "ie+e "e@elopment I%>7%6J.
Homo<2'oit2 +t M129= pol2morp!im i + tron' ri0 ?+$tor ?or t!e "e@elopment o?
(-# I%6,%7J. )n -+p+nee, !omo<2'oit2 +t +not!er PRNP pol2morp!im :2196 i +lo
+ ri0 ?+$tor ?or t!e "e@elopment o? (-# I%8,%9J. :2196 !+ been ?oun" in onl2 Ai+n
+n" P+$i?i$ popul+tion 4!i$! +re more !omo<2'ou ?or met!ionone +t $o"on 129 +
$omp+re" to ;etern popul+tion I27,>0J. )ne??i$ient inter+$tion bet4een !eterolo'ou
PrP
(
mole$ule en$o"e" ?rom "itin$t PRNP +llele (129 M +n" 129 =) m+2 retri$t t!e
$on@erion o? PrP
(
into PrP
*$
. An2 $ontr+int in t!e pro$e o? prion prop+'+tion i
+ume" to lo4 "o4n t!e pro'reion o? t!e "ie+e I%6J. 1!e $lini$+l p!enot2pi$
!etero'eneit2 een in (-# $+e $+n be +ttribute" to "i??erent prion tr+in. A tr+in i
bio$!emi$+ll2 "e?ine" b2 p+ttern +n" r+tio o? PrP
*$
?r+'ment on ;etern blot. 1!ree
M129= 'enot2pe (129 MM, 129 M= +n" 129 ==) +n" 2 tr+in t2pe (t2pe 1 +n" t2pe 2)
$+n be $ouple" into 6 $ombin+tion (MM1, M=1, ==1, MM2, M=2 +n" ==2) 4!i$!
$orrepon" @er2 4ell to "i??erent $lini$+l p!enot2pe o? (-#. En t!e b+i o? t!ee 6
$ombin+tion, t!ree "i??erent tr+in $l+i?i$+tion 2tem !+@e been propoe" I%2,>17>%J.
3atal familial insomnia <33I=
Pre@ioul2 0no4n + t!+l+mi$ "ementi+ but ren+me" in 1986 + ?+t+l ?+mili+l inomni+
(PP)) i +n +utoom+l "omin+ntl2 in!erite" !um+n prion "ie+e. PP) i $+ue" b2 +
PRNP mut+tion #1785 lin0e" to met!ionine o? t!e PRNP pol2morp!im M129=. ;!en
lin0e" to @+line +t t!e $o"on 129, t!e +me mut+tion le+" to + "i@ere p!enot2pe o?
?&'(-# I2%,>>,>5J. *o ?+r, +lmot 100 $+e o? PP) in +lmot >0 ?+milie !+@e been
reporte" ?rom )t+l2, Germ+n2, Autri+, *p+in, .6, Pr+n$e, Pinl+n", t!e .nite" *t+te,
Autr+li+, -+p+n, (!in+, +n" Moro$$o I>6J.
PP) o$$ur eDu+ll2 in men +n" 4omen 4it!out +n2 i'ni?i$+nt "i??eren$e bet4een 129
MM +n" 129 M= 'enot2pe. Ho4e@er, t!e "ie+e "ur+tion m+2 be i'ni?i$+ntl2 !orter
in 129 MM ubMe$t. 1!e PP) $+e preent bet4een 20 +n" 72 2e+r 4it! +n +@er+'e o?
>9 2e+r +n" m+2 li@e +?ter t!e "ie+e onet ?or 8772 mont! 4it! +n +@er+'e o? 18.>
mont!. (lini$+l 2mptom in$lu"e inomni+ or "irupte" leep. M2o$lonu, +t+Li+,
"2+rt!ri+, "2p!+'i+, +n" p2r+mi"+l i'n, +n" +utonomi$ !2per+$ti@+tion $+n +lo be
note". *e@erit2 +n" eDuen$e o? $lini$+l 2mptom m+2 "i??er bet4een 129 MM +n" 129
M= 'enot2pe. )nomni+, m2o$lonu +n" +utonomi$ "2?un$tion +re o?ten more e@ere
in 129 MM ubMe$t, 4!ile +t+Li+, "2+rt!ri+ +n" ei<ure o?ten pre"omin+te in 129 M=
ubMe$t I28,29,>>,>5,>7J.
Pol2omno'r+p!2 i @er2 ue?ul ?or t!e "i+'noi o? t!e "ie+e. )t pro@i"e e@i"en$e o?
inomni+ b2 "ipl+2in' m+r0e" re"u$tion in leep time +n" "ior"erl2 tr+nition bet4een
leep t+'e. 1!e 129 M= 'enot2pe i 0no4n to re"u$e t!e e@erit2 o? t!ee i'n o?
+bnorm+l leep. )n $ontr+t, t!e 129 M= 'enot2pe i +o$i+te" 4it! more 4i"epre+"
!2pomet+bolim in t!e t!+l+mu +n" $in'ul+te $orteL + re@e+le" b2 poitron emiion
tomo'r+p!2 (P:1). 1!u, P:1 m+2 be +not!er ue?ul tool ?or t!e "i+'noi o? PP). ;it!
l+ter $erebr+l $orti$+l +n" $erebell+r in@ol@ement, neuron+l lo +n" +tro'lioi o$$ur
pre"omin+ntl2 in t!e +nterior +n" "orome"i+n t!+l+mi$ nu$lei in +ll $+e +n" in t!e
in?erior oli@e in mot $+e 4it! $+nt PrP "epoition. Ho4e@er, PrP "epoit m+2 be
more e@i"ent in t!e mole$ul+r l+2er o? t!e $erebellum 4it! + trip li0e p+ttern +n" in t!e
ubi$ulum entor!in+l re'ion I28,29,>>,>5,>7J.
&poradic fatal insomnia <s3I=
A por+"i$ ?orm o? ?+t+l inomni+ (P)) 4+ reporte" in 1999. 1!e p+tient !o4e"
$lini$+l +n" neurop+t!olo'i$+l i'n imil+r to PP) but ?+mil2 !itor2 +n" mut+tion in
PRNP 4ere not e@i"ent. All p+tient 4ere 129 MM !omo<2'ote +n" bio$!emi$+l tr+in
t2pin' o? t!ee "ie+e ubt2pe re@e+le" t!e onl2 "i??eren$e in t!e intenit2 o? t!e
un'l2$o2l+te" ?r+'ment o? PrP
*$
t2pe 2; t!e un'l2$o2l+te" ?r+'ment 4+ un"er7
repreente" in PP) I25,>5,>8J. *o ?+r, ne+r 2> P) $+e +ll re@e+lin' 129 MM
!omo<2'oit2 +n" prop+'+tin' PrP
*$
t2pe 2 !+@e been reporte" in @+riou $ountrie o? t!e
4orl" I>9J. P) i o$$+ion+ll2 +lo re?erre" to + g(-#MM2 t!+l+mi$g but i
$lini$op+t!olo'i$+ll2 u??i$ientl2 "itin$t ?rom (-#MM2. )n (-#MM2, $erebr+l $orteL
i mot e@erel2 +??e$te" r+t!er t!+n t!+l+mu 4!ere poibl2 t!e $ir$+"i+n r!2t!m o?
leep74+0e $2$le +re $ontrolle" I>2,>5J. Ho4 t!e +me MM2 PrP
*$
en$o"e "itin$t
p!enot2pe in (-# +n" P) i + m+tter o? $on$ern, in"i$+tin' t!+t ?+$tor +""ition+l to
t!e $o"on 129 'enot2pe +n" PrP
*$
t2pe m+2 +lo be in@ol@e" in t!e "etermin+tion o? prion
tr+in. Ho4e@er, MM2 PrP
*$
$on?ormer +o$i+te" 4it! (-# +n" P) m+2 !o4
@+ri+tion in t!e intenit2 +n" i<e o? t!eir ?r+'ment b2 t!e +ppli$+tion o? more eniti@e
27"imenion+l ele$trop!oreti$ ep+r+tion +n" impro@e" P6 "i'etion $on"ition I>2J.
3amilial or genetic $J" <f0g$J"=
P+mili+l (-# (?(-#) i +o$i+te" 4it! "omin+ntl2 in!erite" point mut+tion in PRNP.
1!ere i + re'ion o? 5 repe+t 4it!in PrP ?rom rei"ue 51791 $omprie" o? + non+pepti"e
POGGGG;GO +n" ?our t+n"em o$t+pepti"e repe+t (PHGGG;GO)>. )nertion o? 279
o$t+pepti"e repe+t (2797EP8)) +n" + "eletion o? 2 o$t+pepti"e repe+t (27EP8#) in
PRNP +re +lo +o$i+te" 4it! u$eptibilit2 to ?(-#. /e$+ue more t!+n 50U o? ?(-#
$+e !+@e been reporte" 4it!out + poiti@e ?+mil2 !itor2 o? t!e "ie+e, t!e term
g'eneti$ (-# ('(-#)g i no4 bein' ue" more ?reDuentl2 inte+" o? ?(-#. 1!ere i mu$!
@+ri+tion in t!e penetr+n$e o? "i??erent mut+tion + e@i"en$e" b2 $oni"er+ble
intr+?+mili+l +n" intr+'ener+tion+l p!enot2pi$ @+ri+bilit2; ometime, t!e "ie+e m+2
0ip + 'ener+tion. 1!e in$i"en$e o? '(-# i 5715U o? +ll (-# $+e. Alt!ou'! t!e
?+mili+l n+ture o? '(-# i 0no4n in$e 1920, mut+tion +o$i+te" 4it! t!e "ie+e 4ere
?irt reporte" in 1989 onl2 2 2e+r +?ter t!e $lonin' o? PRNP $#5A I28,29,>2,>>,>7,50J.
1!e ?reDuen$2 o? mut+tion "i??er 4orl"4i"e; !o4e@er, 'eo'r+p!i$+l or et!ni$ $luter
o? '(-# $+e 4it! mut+tion :2006, )210=, #1785, +n" =180) !+@e been reporte"
?rom )r+el, *lo@+0i+, (!ile, )t+l2, *p+in +n" -+p+n I>2,51J.
*imil+r to (-#, t!e $lini$op+t!olo'i$+l p!enot2pe in '(-# l+r'el2 $orrel+te 4it! t!e
$o"on 129 'enot2pe +n" PrP
*$
t2pe, +n" mut+tion +ppe+r to pl+2 + role not more t!+n +
u$eptibilit2 ?+$tor. ;!et!er PRNP pol2morp!im ot!er t!+n M129= +lo in?luen$e t!e
"ie+e $!+r+$teriti$ i un0no4n. Multiple tr+in, +lt!ou'! 2et rem+in uni"enti?ie",
m+2 be in@ol@e" in t!e p+t!o'enei o? t!e "ie+e. Por ome '(-# $+e, ?r+'ment o?
12718.5 0#+ in +""ition to ?r+'ment o? 19 +n" 21 0#+ 4!i$! $!+r+$teri<e PrP
*$
t2pe 2
+n" 1, repe$ti@el2, $+n +lo be ?oun". PRNP mut+tion m+2 pl+2 t!eir p+rt in t!e
p+t!o'enei o? '(-# b2 i) in$re+in' t!e propenit2 o? PrP
(
+n" PrP
M
?or +''re'+tion, ii)
in$re+in' t!e retention o? +''re'+te" PrP mole$ule 4it!in e$retor2 p+t!4+2, +n" iii)
mo"ul+tin' t!e intr+mole$ul+r +lt7bri"'e +n" !2"ro'en bon" inter+$tion. #iturb+n$e in
intr+mole$ul+r inter+$tion i 0no4n to proMe$t t!e !2"rop!obi$ +mino +$i" outi"e
m+0in' t!e protein inoluble I>>J. ;it! in$re+e o? e@er2 EP8, bot! t!e +bilit2 o? PrP
M
?or bin"in' "i@+lent ion u$! + $opper +n" t!e e@erit2 o? $lini$op+t!olo'i$+l p!enot2pe
+re in$re+e". 1!e bio$!emi$+l tr+in t2pin' o? '(-# o?ten re@e+l t!e
un"errepreent+tion o? un'l2$o2l+te" ?r+'ment. 1!i i be$+ue un'l2$o2l+te"
?r+'ment +re more unt+ble t!+n mono7 +n" "i'l2$o2l+te" ?r+'ment +n" +re, t!ere?ore,
more ine??i$ient in t!eir tr+nport ?rom e$retor2 p+t!4+2 to t!e pl+m+ membr+ne
I>2,>>,52J. Alt!ou'! $lini$+l p!enot2pe rel+te" to mot o? mut+tion o@erl+p 4it! t!oe
o? (-# I>2J, t!e $lini$+l p!enot2pe in '(-# $+e $+rr2in' t!e 118%A7129M !+plot2pe
i li'!tl2 "itin$ti@e +n" in$orpor+te peron+lit2 $!+n'e ?ollo4e" b2 r+pi"l2
pro'rei@e "ementi+, 4it! ?ronto7tempor+l ?e+ture u$! + +''rei@e be!+@ior,
!2peror+lit2, @erb+l tereot2pe +n" o?ten p+r0inoni+n i'n I5%J.
Gerstmann-&tr>ussler-&cheinker syndrome <G&&=
Autoom+l "omin+nt in!erit+n$e o? PRNP mut+tion m+2 +lo le+" to +not!er ?orm o?
!um+n 1*: n+me" + Gertm+nn7*trùler7*$!ein0er *2n"rome (G**). 1!e in$i"en$e
o? G** i 1 in 100 million o? popul+tion per 2e+r I28J. G** i $!+r+$teri<e" b2 +n e+rl2
onet bet4een %0 +n" 60 2e+r o? +'e +n" lo4 "ie+e pro'reion eLten"e" o@er +
perio" o? %.579.5 2e+r. (lini$+l 2mptom 4!i$! m+2 !o4 intr+?+mili+l +n"
intr+'ener+tion+l @+ri+tion in$lu"e $erebell+r +t+Li+, '+it +bnorm+litie, "ementi+,
"2+rt!ri+, o$ul+r "2metri+, in?reDuent m2o$lonu, p+ti$ p+r+p+rei, p+r0inoni+n
i'n, +n" !2pore?leLi+ or +re?leLi+ in t!e lo4er eLtremitie I28,29J. Ho4e@er, le'
!2perre?leLi+ ?rom +n e+rl2 "ie+e $oure !+ re$entl2 been een in + -+p+nee G**
p+tient $+rr2in' t!e P1023 mut+tion I5>J. )n G**, +ltere" leep +n" temper+ture r!2t!m
m+2 +lo be noti$e" I55J. 1!e PRNP pol2morp!im M129= !+ been !o4n to in?luen$e
t!e "ie+e p!enot2pe. ;!en lin0e" to =129 +llele, P1023, 4!i$! i t!e mot $ommon
$+ue o? G**, reulte" in t!e pre"omin+n$e o? p2$!i+tri$ i'n u$! + +p+t!2 +n"
"epreion I56J. ::G i r+rel2 "i+'noti$ in G**. Pollo4in' PRNP mut+tion !+@e been
!o4n to $oe're'+te 4it! G**: P1023, P1053, A117=, Y1>5^, O160^, P198*, O2178,
Y2185, Y226^ +n" O227^ I28,29,57J. Y2185 "emontr+te" $lini$+l $riteri+ ?or poible
Al<!eimer "ie+e +n" poible ?rontotempor+l "ementi+, 4it! neuro?ibrill+r2
"e'ener+tion on neurop+t!olo'i$+l pro?ile, +n" @+riou PrP
*$
?r+'ment in t!e r+n'e o?
10780 0#+ I58J. )n 'ener+l, neurop+t!olo'i$ ?e+ture o? G** p+tient in$lu"e numerou
+m2loi" pl+Due, e@ere to +bent pon'i?orm $!+n'e, neuron+l lo, +tro$2ti$
mi$ro'lioi, +n" @+ri+ble nuero?ibrill+r2 t+n'le I28,29,59J.
Iatrogenic $J" <i$J"=
)+tro'eni$ (-# (i(-#) 4+ ?irt "e$ribe" in 197> in + peron 4!o re$ei@e" $+"+@eri$
$orne+l tr+npl+nt ?rom + p+tient o? (-# I22J. *e@er+l $+e o? !um+n prion "ie+e, in$e
t!en, !+@e been +o$i+te" 4it! i+tro'eni$ tr+nmiion o? (-# b2 t!e ue o? tereot+$ti$
intr+$erebr+l ::G nee"le or neurour'i$+l intrument, $+"+@eri$ "ur+ m+ter 'r+?t +n"
intr+mu$ul+r inMe$tion o? $ont+min+te" $+"+@eri$ pituit+r27"eri@e" !um+n 'ro4t!
!ormone (!GH) +n" 'on+"otrop!in !ormone. 1!e !i'!et proportion o? i(-# $+e i
+ttribute" to tre+tment 4it! !GH +n" 32o"ur+ 'r+?t pro"u$e" b2 /. /r+un Melun'en
AG o? Germ+n2 +n" pro$ee" be?ore M+2 1987. Mot o? (-# $+e lin0e" to tre+tment
4it! !GH !+@e o$$urre" in Pr+n$e, 4!ile t!oe lin0e" to tre+tment 4it! "ur+ m+ter 'r+?t
!+@e m+inl2 o$$urre" in -+p+n I28,29,51,60J. /et4een t!e l+te 1950 +n" 1985, +bout
%0,000 $!il"ren 4ere tre+te" 4it! !GH 4orl"4i"e, +n" t!e o@er+ll proportion o? (-#
$+e ?rom t!e tre+te" popul+tion !+ been etim+te" to be +bout 1&100. )t i belie@e" t!+t
t!e li0el2 PrP
*$
$ont+min+tion o? pituit+r27"eri@e" !GH +n" "ur+ m+ter 'r+?t reulte"
?rom t!e pr+$ti$e o? b+t$! pro$ein'. /e?ore t!e pro"u$tion o? re$ombin+nt !GH, it 4+
+ p!+rm+$euti$+l pr+$ti$e to pro$e 5,000720,000 $+"+@eri$ pituit+r2 'l+n" in + in'le
b+t$! ?or t!e eLtr+$tion o? t!e !ormone. 1!e preen$e in t!e b+t$! o? + ?e4 pituit+r2
'l+n" ?rom un0no4n (-# $+e m+2 be reponible ?or $ont+min+tion. ;it! t!e
+@+il+bilit2 o? re$ombin+nt !GH +n" t!e initi+tion o? ep+r+te" pro$ein' o? in"i@i"u+l
"ur+ m+ter 'r+?t in$e 1987, t!e prob+bilit2 o? o$$urrin' ?uture i(-# $+e +ppe+r to be
@er2 lo4. A pe+0 in t!e in$i"en$e o? i(-# $+e 4it! lon' in$ub+tion perio" m+2 o$$ur,
!o4e@er I28,29,60J.
1!e $lini$op+t!olo'i$+l ?e+ture o? (-# lin0e" to tre+tment 4it! !GH reemble 4it!
t!oe o? 0uru. 1!e 129 MM !omo<2'oit2 i + ri0 ?+$tor +n" in$ub+tion perio" m+2 be
in t!e r+n'e o? >.5 to o@er 25 2e+r 4it! + me+n o? 12 2e+r I28,29,60,61J. )n $ontr+t, t!e
$lini$op+t!olo'i$+l ?e+ture o? (-# lin0e" to neuro'r+?tin' o? "ur+ m+ter or t!e ue o?
neurour'i$+l intrument reemble 4it! t!oe o? (-#. 1!e me+n "ur+tion o? illne i
18 mont! +n" t!e in$ub+tion perio" m+2 be in t!e r+n'e o? 1.5718 2e+r 4it! + me+n o?
+bout 6 2e+r. )n -+p+n, t!e minimum ri0 o? "e@elopin' i(-# !+ been etim+te" to be
+pproLim+tel2 1&%000 32o"ur+ 'r+?t re$ipient I28,29,60J.
/uru
6uru i t!e ?irt !um+n prion "ie+e t!+t 4+ !o4n to be tr+nmiible to $!imp+n<ee
b2 intr+$erebr+l intro"u$tion o? br+in !omo'en+te ?rom 0uru p+tient I62J. 6uru !+
o$$urre" eL$lui@el2 in t!e Pore lin'uiti$ 'roup o? P+pu+ 5e4 Guine+ :+tern
Hi'!l+n" +n" t!e nei'!borin' people 4it! 4!om t!e2 interm+rrie". 1!ere 4+ +
pr+$ti$e +mon' t!ee 'roup to $onume t!e "e+" bo"ie o? t!eir rel+ti@e + + m+r0 o?
repe$t +n" mournin' (ritu+liti$ $+nnib+lim). ;omen +n" 2oun' $!il"ren o? bot! eLe
4ere more eLpoe" to t!e ri0 m+teri+l u$! + br+in +n" @i$er+ t!+n +"ult men 4!o
uu+ll2 !+" pre?erenti+ll2 to $onume mu$le. 1!e 0uru epi"emi$ 0ille" 172U o? t!e
popul+tion +t it pe+0. *ome @ill+'e be$+me e@en "e@oi" o? +"ult 4omen. ;it! + b+n on
ritu+liti$ $+nnib+lim in t!e mi"71950 impoe" b2 Autr+li+n +ut!oritie, t!e in$i"en$e
o? t!e "ie+e t+rte" to "e$line te+"il2. 6uru 4+ intro"u$e" to ;etern me"i$ine in l+te
1950, +lt!ou'! t!e ?irt $+e o? 0uru 4+ ober@e" +roun" 1920. 1!e ;etern $ientit
4ere @er2 oon +ble to pro@e ritu+liti$ $+nnib+lim + t!e etiolo'2 o? t!e "ie+e. 1!e
ol"er 0uru p+tient 4!o eLperien$e" +n eLpoure to t!e in?e$tion be?ore t!e b+n $+n till
be een. 1!e in$ub+tion perio" o? 0uru in u$! p+tient 4oul" be more t!+n 50 2e+r
I27,59,6%765J. 6uru !+ impoe" tron' ele$tion preure in t!e +??e$te" Pore 'roup on
PRNP epe$i+ll2 +t $o"on 127 +n" 129. Hetero<2'oit2 +t t!ee PRNP $o"on i +
reit+n$e ?+$tor ?or 0uru +n" $+n be een 4it! m+r0e" pre@+len$e +mon' ur@i@or o? t!e
0uru epi"emi$ I27,65J.
6uru !+ % $lini$+l t+'e n+mel2 +mbul+nt (till $+n 4+l0), e"ent+r2 (onl2 $+n it up),
+n" termin+l (un+ble to it up in"epen"entl2). An ill7"e?ine" pro"rom+l perio"
$!+r+$teri<e" b2 !e+"+$!e +n" p+in uu+ll2 in t!e Moint o? le' m+2 pre$e"e t!ee t+'e.
(erebell+r +t+Li+, tremor +n" $!orei?orm +n" +t!etoi" mo@ement +re "itin$ti@e +n"
prominent $lini$+l i'n. *!i@erin' +mpli?i+ble b2 $ol" 4+ t!e 2mptom on t!e b+i o?
4!i$! t!e "ie+e 4+ n+me" g0urug. 1!e mot prominent $lini$+l ?e+ture o? (-#, t!e
"ementi$ illne $+n +lo o$$ur in ome $+e but it !+ppen "urin' t!e ?in+l "ie+e
t+'e onl2. 5europ+t!olo'i$+l ?e+ture u$! + pon'ioi, neuron+l lo, +n" +tro$2ti$
mi$ro'lioi $+n @+ri+bl2 be ober@e" in (5* uu+ll2 in t!e 're2 m+tter. 1!e PrP
*$
"epoition i ober@e" in (5* onl2 I59,6%J. 1!e neurop+t!olo'i$+l propert2 4!i$!
"itin'ui!e 0uru ?rom (-# i t!e preen$e o? numerou 0uru pl+Due, p!eri$+l bo"ie
4it! + rim o? r+"i+tin' ?il+ment. 6uru i belie@e" to be $+ue" b2 t!e $onumption o? +
(-# $+e +n" eLperiment+l tr+nmiion tu"ie !+@e !o4n imil+rit2 bet4een t!e
mole$ul+r +n" p+t!obiolo'i$+l propertie o? prion $+uin' 0uru, (-# +n" i(-# I66J.
*imil+r tu"ie !+@e +lo re@e+le" "i??eren$e in tr+nmiion "2n+mi$, perip!er+l
p+t!o'enei +n" t!e neurop+t!olo'2 propertie o? 0uru +n" @(-# prion. A bot! 0uru
+n" @(-# +re $+ue" b2 in?e$tion @i+ or+l route, t!ee "i??eren$e $+n be +ttribute" to t!e
tr+in t2pe r+t!er t!+n t!e route o? in?e$tion I6%J. Ho4e@er, + re$ent tu"2 !o4e" t!+t
(-#, /*: +n" $r+pie +'ent 4ere e@i"entl2 "i??erent ?rom t!e 0uru +'ent in in$ub+tion
time, br+in neurop+t!olo'2, +n" t!e l2mp!oreti$ul+r in@ol@ement. 1!e +ut!or $on$lu"e"
t!+t gt!e 'eo'r+p!i$ in"epen"en$e o? t!e 0uru +'ent pro@i"e +""ition+l re+on to
eLplore $+u+l en@ironment+l p+t!o'en in t!ee in?e$tiou neuro"e'ener+ti@e "ie+eg
I67,68J.
,ariant $J" <7$J"=
1!e ?irt 10 p+tient o? ne4 @+ri+nt or impl2 o? @+ri+nt (-# (n@(-#&@(-#) 4ere
reporte" in April 1996 in .6 I2>,60J. 1!e +'e o? t!ee p+tient 4+ rel+ti@el2 2oun'er
bet4een 16 +n" %9 2e+r +n" t!e2 m+ni?ete" + pre"omin+n$e o? p2$!i+tri$ 2mptom
inte+" o? $erebell+r +t+Li+ or pro'rei@e "ementi+ I60J. About 219 @(-# $+e !+@e
been reporte" !it!erto ?rom 8 :urope+n +n" > non7:urope+n $ountrie (.*A, (+n+"+,
*+u"i Ar+bi+, +n" -+p+n). 1!e mot o? @(-# $+e (172) !+@e been reporte" ?rom .6
+lone I69J. P2$!i+tri$ +n" be!+@ior+l 2mptom o? @(-# m+2 in$lu"e +'it+tion,
+''reion, "epreion, +nLiet2, +p+t!2, emotion+l l+bilit2, inomni+, poor $on$entr+tion,
p+r+noi" "eluion, re$0lene, or 4it!"r+4+l; + $ombin+tion o? t4o or more o? t!ee
2mptom +ppe+r in mot o? t!e p+tient. *ome p+tient m+2 +lo !o4 i'n o? enor2
"iturb+n$e u$! + p+in, p+ret!ei+, +n" "2et!ei+. 1!e neurolo'i$ 2mptom o$$ur +t
le+t 6 mont! +?ter t!e onet o? p2$!i+tri$ 2mptom +n" in$lu"e $erebell+r +t+Li+,
$o'niti@e imp+irment, in@olunt+r2 mo@ement 4!i$! m+2 be "2toni$, $!orei?orm or
m2o$loni$. )n$ontinen$e o? urine, pro'rei@e immobilit2, +n" +0ineti$ mutim +re t!e
l+te onet i'n. #e+t! o?ten o$$ur be$+ue o? inter$urrent in?e$tion. 1!e me+n +'e +t
onet o? 2mptom i 29 2e+r, +n" t!e pro'reion or tot+l "ur+tion o? t!e "ie+e p+n
18 mont! in +@er+'e, 4!i$! i imil+r to t!+t i reporte" ?or 0uru +n" i(-# lin0e" to
tre+tment 4it! !GH I28,29,60J. Gener+li<e" lo4in' o? ::G +$ti@it2 +n" +n in$re+e in
t!e le@el o? 1>7%7% protein in (*P m+2 be "i+'noti$ o? @(-# in more t!+n 50U o? t!e
$+e. Ho4e@er, t!e ober@+tion o? poterior t!+l+mi$ !i'! i'n+l $!+r+$teri<e" b2
Npul@in+rN or N!o$0e2 ti$0N i'n on 12 "i??uion or Pl+ir 4ei'!te" M8) im+'in' +n" t!e
"ete$tion o? PrP
re
in tonill+r biop2 +re import+nt ?or t!e pe$i?i$ "i+'noi o? t!e
"ie+e I29,70J.
1!e neurop+t!+lo'i$+l !+llm+r0 o? @(-# i t!e preen$e o? 0uru7t2pe +m2loi" pl+Due
urroun"e" b2 pon'i?orm leion gt!e ?lori" pl+Dueg 4!i$! +lo !+@e been een in
$r+pie but ne@er in ot!er !um+n prion "ie+e I28,29,60J. *pon'i?orm $!+n'e o$$ur
mot e@i"entl2 in t!e b++l '+n'li+ +n" t!+l+mu 4it! p+re "itribution t!rou'!out t!e
$erebr+l $orteL. 1!e ?lori" pl+Due +n" PrP
re
immuno!ito$!emi$+l t+inin' !+@e
o$$urre" pre"omin+ntl2 in t!e $erebellum +n" $erebrum I28J. Ho4e@er, u??i$ient
+mount o? PrP
re
+re "ete$te" in t!e l2mp!oreti$ul+r 2tem o? @(-# p+tient I60J. 1!e
"ete$tion o? PrP
re
in t!e l2mp!oreti$ul+r 2tem !+ $on?i"entl2 been ue" ?or t!e
"i+'noi o? @(-# e@en in $lini$+ll2 norm+l ubMe$t ($+rrier) I71J. 1o "+te, +ll @(-#
p+tient !+@e been 129 MM !omo<2'ote I72J.
=er2 oon +?ter t!e report on 10 @(-# $+e, epi"emiolo'i$+l tu"ie, eLperiment+l
tr+nmiion o? t!e "ie+e to $2nomolo'ou m+$+Due +n" mi$e (4il" + 4ell +
tr+n'eni$) +n" bio$!emi$+l tr+in t2pin' lin0e" t!e etiolo'2 o? @(-# to in?e$tion ?rom
/*: prion I60J. 1!e +me or "i@ere p!enot2pe m+2 "e@elop on prim+r2 +n" e$on"+r2
tr+nmiion o? @(-# +n" /*: to mi$e eLprein' !um+n PrP, "epen"in' on t!e our$e
o? ino$ulum +n" t!e PrP eDuen$e o? t!e re$ipient, +n" t!e 129 M= !etero<2'ote m+2 be
le reit+nt to @(-# tr+nmiion + $omp+re" to /*: tr+nmiion I7%,7>J. 1!e :2196
!etero<2'oit2 4!i$! !+ been $oni"ere" + ri0 ?+$tor ?or tr+nmiion o? /*: to
!um+n m+2 $on?er reit+n$e to @(-# tr+nmiion 4it!in !um+n I70,75J. Moreo@er, +t
le+t > p+t!olo'i$+ll2 $on?irme" $+e in$lu"in' 1 4it! ub$lini$+l or potenti+ll2
pre$lini$+l in?e$tion !+@e been +o$i+te" 4it! t!e e$on"+r2 @(-# tr+nmiion @i+
bloo" tr+n?uion I76J. 1!ee report on e$on"+r2 i+tro'eni$ tr+nmiion +n" t!e
poibilit2 o? @(-# o$$urren$e 4it! lon' in$ub+tion perio" in in"i@i"u+l 4it! 129 M=
+n" 129 == PrP 'enot2pe !+@e r+ie" eriou publi$ !e+lt! $on$ern I71,72,77,78J.
*ome $+e o? 0uru +n" i(-# !+@e o$$urre" +?ter in$ub+tin' t!e "ie+e ?or +lmot 50
+n" %0 2e+r, repe$ti@el2 I6%,6>,76,79J.
,ariably protease-sensiti7e prionopathy <,P&Pr=
)n 2008, + no@el ?orm o? +t2pi$+l "ementi+ 4+ "emontr+te" in 11 p+tient, +ll o? 4!om
4ere 129 == !omo<2'ote +n" mot o? 4!om re@e+le" + poiti@e ?+mil2 !itor2 ?or
$o'niti@e imp+irment. 5o mut+tion in PRNP +""ition+l to t!e M129= pol2morp!im 4+
"ete$te". 1!e $lini$+l $oure o? t!e "ie+e 4+ 2 2e+r lon'er t!+n (-# but
neurop+t!olo'i$+l pro?ile 4ere "i+'noti$ o? 1*:. A more "itin$ti@e ?e+ture b+e" on
4!i$! t!e "ie+e 4+ n+me" initi+ll2 + gprote+e7eniti@e prionop+t!2g (P*Pr) 4+ t!e
re"u$e" reit+n$e o? PrP
#i
io?orm to proteol2i b2 P6. 1!e proteol2i o? PrP
#i
io?orm b2 P6 reulte" in more t!+n % PrP
#i
?r+'ment. Ampli?i$+tion b2 PM(A +n"
tr+nmiibilit2 to +nim+l mo"el o? PrP
#i
2et rem+in to be in@eti'+te" I26,>2J. 1!ee
tu"ie 4ill +lo in?orm on mole$ul+r me$!+nim o? t!e "ie+e p+t!o'enei.
*imil+r to (-#, P*Pr $+n be een in in"i@i"u+l !+rborin' +n2 o? % M129= 'enot2pe
(129 MM, 129 M= +n" 129 ==). A t!e eniti@it2 o? PrP
#i
io?orm to tre+tment 4it!
P6 4+ @+ri+ble +$$or"in' to t!e $o"on 129 'enot2pe, t!e "ie+e 4+ ren+me" +
g@+ri+bl2 prote+e7eniti@e prionop+t!2g (=P*Pr). 1!e PrP
#i
?rom 129 == $+e 4+
more eniti@e to P6 tre+tment t!+n 4+ PrP
#i
?rom 129 MM $+e, 4it! PrP
#i
?rom 129
M= $+e !o4in' interme"i+r2 P6 eniti@it2 I80J. Moreo@er, b+e" on t!e $o"on 129
'enot2pe, t!e PrP
#i
$on?ormer ?rom =P*Pr $+e not onl2 !o4e" "i??erenti+l
immunore+ti@it2 to mono$lon+l +ntibo"ie r+ie" +'+int @+riou PrP epitope but +lo
@+rie" in t!e intenit2 (r+tio) o? in"i@i"u+l ?r+'ment. ;!et!er t!e $o"on 129 'enot2pe
+re +o$i+te" 4it! "itin$t $lini$+l p!enot2pe, neurop+t!olo'i$+l leion +n"
!itolo'i$+l "itribution o? PrP
#i
rem+in to be elu$i"+te". 1o "+te, %0 $+e 4it! =P*Pr
in$lu"in' 20 o? 129 ==, 7 o? 129 M= +n" % o? 129 MM PRNP 'enot2pe !+@e been
reporte" ?rom @+riou $ountrie I>2,80782J. A$$or"in' to t!i "+t+, t!e PRNP 'enot2pe
129 MM +ppe+r prote$ti@e +'+int t!e "e@elopment o? =P*Pr I>2J.
Go to:
$onclusion
1!e epi"emi$ o? 0uru, i+tro'eni$ (-# +n" @(-# !+@e re+$!e" t!eir en" I8%J. Ho4e@er,
por+"i$ +n" 'eneti$ $+e o? !um+n prion "ie+e +re o$$urrin' 4orl"4i"e 4it! +n
+nnu+l pre@+len$e o? 172 $+e per million o? popul+tion. Amon' 'eneti$ !um+n prion
"ie+e, G** preent pre"omin+ntl2 + +n +m2loi"op+t!2. 1!ere i no $ure ?or t!ee
"ior"er. Mot o? "e@elopin' $ountrie in$lu"in' P+0it+n !+@e no epi"emiolo'i$+l
in?orm+tion on !um+n prion "ie+e. ;e !+@e re$entl2 per?orme" t!e +n+l2i o? PRNP
in 909 unrel+te" P+0it+ni in"i@i"u+l. An inertion o? % o$t+pepti"e repe+t (%7EP8))
4+ ?oun" in !etero<2'ou t+te in +n in"i@i"u+l +n" t!e eLtent o? !omo<2'oit2 +t t!e
129 $o"on 4+ 6%U. 1!ee reult in"i$+te t!+t P+0it+ni popul+tion i u$eptible to
prion "ior"er I8>J. 1!e o$t+pepti"e repe+t re'ion o? !um+n PRNP $onit o? 5 repe+t
4!i$! +re "ei'n+te" + 81 t!rou'! 85. )? +n2 nu$leoti"e @+ri+tion i ?oun" 4it!in +
repe+t, t!e n+me o? t!+t nu$leoti"e i +""e" to t!e n+me o? $orrepon"in' repe+t i.e., 82+
or 8%' I85J. A %7EP8) (81, 82, 82, 8%', 82, 82, 8%, 8>) lin0e" to 219 6 +llele in one
peron (68 2e+r ol") +n" to 129 = +llele in +not!er (69 2e+r ol") !+ been +o$i+te"
4it! ?&'(-# I86,87J. A %7EP8) (81, 82, 82, 82+, 82, 82, 8%, 8>) lin0e" to 129 M +llele
!+ +lo been "ete$te" in + $lini$+ll2 norm+l (!inee 2oun' 'irl +n" !er mot!er 4!o 4+
in !er l+te %0N I85J.
Go to:
Abbre7iations
PRNP: Prion protein 'ene; PrP: Prion protein; PrP
(
: (ellul+r io?orm o? prion protein;
PrP
*$
: *$r+pie io?orm o? prion protein; PrP
M
: Mut+nt PrP; 1*:(): 1r+nmiible
pon'i?orm en$ep!+lop+t!2(ie); (-#: (ruet<?el"t7-+$ob "ie+e; (-#: *por+"i$ (-#;
@(-#: =+ri+nt (-#; ?&'(-#: P+mili+l&'eneti$ (-#; i(-#: )+tro'eni$ (-#; PP): P+t+l
?+mili+l inomni+; G**: Gertm+nn7*tr+uler7*$!ein0er 2n"rome; P): *por+"i$ ?+t+l
inomni+; P*Pr: Prote+e7eniti@e prionop+t!2; =P*Pr: =+ri+bl2 prote+e7eniti@e
prionop+t!2; 1M:: 1r+nmiible min0 en$ep!+lop+t!2; (;#: (!roni$ 4+tin' "ie+e;
/*:: /o@ine pon'i?orm en$ep!+lop+t!2; :.:: :Loti$ un'ul+te pon'i?orm
en$ep!+lop+t!2; P*:: Peline pon'i?orm en$ep!+lop+t!2; 5HP: 1*: in non7!um+n
prim+te; EP8: E$t+pepti"e repe+t; EP8): )nertion o? o$t+pepti"e repe+t; EP8#:
#eletion o? o$t+pepti"e repe+t; GP): Gl2$o2lp!op!+ti"2linoitol; (5*: (entr+l
ner@ou 2tem; ::G: :le$troen$ep!+lo'r+p!2; (*P: (erebropin+l ?lui"; (1: (omputer
tomo'r+p!2; M8): M+'neti$ reon+n$e im+'in'; P:1: Poitron emiion tomo'r+p!2;
P6: Protein+e 6; $#5A: (omplement+r2 #5A; !GH: Hum+n 'ro4t! !ormone; re:
8eit+nt; #i: #ie+e; 0b: 6ilo b+e; 0#+: 6ilo #+lton; ++: Amino +$i"; A: Al+nine;
#: Ap+rti$ +$i"; :: Glut+mi$ +$i"; P: P!en2l+l+nine; G: Gl2ine; H: Hiti"ine; ):
)oleu$ine; 6: 32ine; 3: 3eu$ine; M: Met!ionine; 5: Ap+r+'ine; P: Proline; O:
Glut+mine; 8: Ar'inine; *: *erine; 1: 1!reonine; =: =+line; ;: 1r2ptop!+n; ^: *top
$o"on; Y: 12roine.
Go to:
$ompeting interests
1!e +ut!or "e$l+re t!+t t!e2 !+@e no $ompetin' interet.
Go to:
Authors? contributions
M)
1
ur@e2e" liter+ture +n" 4rote t!e +rti$le. *M
2
or'+ni<e" t!e $ontent +n" ubmitte"
t!e +rti$le. All +ut!or re+" +n" +ppro@e" t!e ?in+l m+nu$ript.
Go to:
eferences
1. 3in"en 8, M+rtin =8, Pr+"o MAM, (+mm+rot+ M, )<Duier"o ), /rent+ni 88.
P!2iolo'2 o? t!e prion protein. P!2iol 8e@. 2008;88:67%728. "oi:
10.1152&p!2re@.00007.2007. IPubMe"J I(ro 8e?J
2. P+n 6M, /+l"4in M, 5'u2en -, G+et M, *erb+n A, Grot! #, Me!l!orn ),
Hu+n' A, Pletteri$0 8-, (o!en P:, Pruiner */. (on@erion o? +lp!+7!eli$e into
bet+7!eet ?e+ture in t!e ?orm+tion o? t!e $r+pie prion protein. Pro$ 5+tl A$+"
*$i .*A. 199%;90:1096210966. "oi: 10.107%&pn+.90.2%.10962. IPM( ?ree
+rti$leJ IPubMe"J I(ro 8e?J
%. Pruiner */. Prion. Pro$ 5+tl A$+" *$i .*A. 1998;95:1%%6%1%%8%. "oi:
10.107%&pn+.95.2%.1%%6%. IPM( ?ree +rti$leJ IPubMe"J I(ro 8e?J
>. *mirno@+ =, /+ron G*, E??er"+!l #6, 8+2mon" G-, (+u'!e2 /, *ure4i$< ;6.
*tru$tur+l or'+ni<+tion o? br+in7"eri@e" m+mm+li+n prion eL+mine" b2
!2"ro'en7"euterium eL$!+n'e. 5+t *tru$t Mol /iol. 2011;18:50>506. "oi:
10.10%8&nmb.20%5. IPM( ?ree +rti$leJ IPubMe"J I(ro 8e?J
5. A+!n 8, 3iu A, 3u!r 1, 8ie0 8, @on *$!roetter (, 3ope< G+r$i+ P, /illeter M,
(+l<ol+i 3, ;i"er G, ;ut!ri$! 6. 5M8 olution tru$ture o? t!e !um+n prion
protein. Pro$ 5+tl A$+" *$i .*A. 2000;97:1>5150. "oi: 10.107%&pn+.97.1.1>5.
IPM( ?ree +rti$leJ IPubMe"J I(ro 8e?J
6. (ollin'e -, (l+r0e A8. A 'ener+l mo"el o? prion tr+in +n" t!eir p+t!o'eni$it2.
*$ien$e. 2007;%18:9%09%6. "oi: 10.1126&$ien$e.11%8718. IPubMe"J I(ro
8e?J
7. A'u<717
>159.2006.0%909.L. IPubMe"J I(ro 8e?J
8. )mr+n M, M+!moo" *. An o@er@ie4 o? +nim+l prion "ie+e. =irol -. 2011;8:>9%.
"oi: 10.1186&17>%7>22^787>9%. IPM( ?ree +rti$leJ IPubMe"J I(ro 8e?J
9. M+r! 8P, H+"lo4 ;-. 1r+nmiible min0 en$ep!+lop+t!2. 8e@ *$i 1e$!.
1992;11:5%9550. IPubMe"J
10. *i'ur"on (-, Miller M;. Et!er +nim+l prion "ie+e. /rit Me" /ull.
200%;66:199212. "oi: 10.109%&bmb&66.1.199. IPubMe"J I(ro 8e?J
11. ;illi+m :*, Youn' *. (!roni$ 4+tin' "ie+e o? $+pti@e mule "eer: +
pon'i?orm en$ep!+lop+t!2. - ;il"l #i. 1980;16:8998. IPubMe"J
12. ;ell GAH, *$ott A(, -o!non (1, Gunnin' 8P, H+n$o$0 8#, -e??re2 M,
#+4on M, /r+"le2 8. A no@el pro'rei@e pon'i?orm en$ep!+lop+t!2 in $+ttle.
=et 8e$. 1987;121:>19>20. "oi: 10.11%6&@r.121.18.>19. IPubMe"J I(ro 8e?J
1%. 6ir04oo" -6, (unnin'!+m AA, ;ell GA, ;ilemit! -;, /+rnett -:.
*pon'i?orm en$ep!+lop+t!2 in + !er" o? 're+ter 0u"u (1r+'el+p!u trepi$ero):
epi"emiolo'i$+l ober@+tion. =et 8e$. 199%;1%%:%60%6>. "oi:
10.11%6&@r.1%%.15.%60. IPubMe"J I(ro 8e?J
1>. 6ir04oo" -6, (unnin'!+m AA. :pi"emiolo'i$+l ober@+tion on pon'i?orm
en$ep!+lop+t!ie in $+pti@e 4il" +nim+l in t!e /riti! )le. =et 8e$.
199>;1%5:296%0%. "oi: 10.11%6&@r.1%5.1%.296. IPubMe"J I(ro 8e?J
15. ;2+tt -M, Pe+ron G8, Gru??2""7-one 1-. Peline pon'i?orm en$ep!+lop+t!2.
Peline Pr+$t. 199%;21:79.
16. /on 5, Metre7Pr+n$e 5, /elli P, (+t!+l+ P, G+M"ue0 #(, /ro4n P. 5+tur+l
+n" eLperiment+l or+l in?e$tion o? non!um+n prim+te b2 bo@ine pon'i?orm
en$ep!+lop+t!2 +'ent. Pro$ 5+tl A$+" *$i .*A. 1999;96:>0>6>051. "oi:
10.107%&pn+.96.7.>0>6. IPM( ?ree +rti$leJ IPubMe"J I(ro 8e?J
17. G+M"ue0 #(, Ai'+ =. #e'ener+ti@e "ie+e o? t!e $entr+l ner@ou 2tem in
5e4 Guine+. 1!e en"emi$ o$$urren$e o? g0urug in t!e n+ti@e popul+tion. 5e4
:n'l - Me". 1957;257:97>978. "oi: 10.1056&5:-M1957111>2572005.
IPubMe"J I(ro 8e?J
18. (reut<?el"t HG. .g ber eine ei'en+rti'e !er"?ogrmi'e :r0r+n0un' "e
Aentr+lner@en2tem. A Ge+mte 5eurol P2$!i+tr. 1920;57:119. "oi:
10.1007&/P02866081. I(ro 8e?J
19. -+0ob A. .g ber ei'en+rti'e :r0r+n0un'en "e Aentr+lner@en2tem mit
bemer0en4ertem +n+tomi$!em. /e?un"e. (*p+ti$!e Peu"o0leroe7
:n$ep!+lom2elop+t!ie mit "ieminierten #e'ener+tion!er"en) A Ge+mte
5eurol P2$!i+tr. 1921;6>:1>7228. "oi: 10.1007&/P028709%2. I(ro 8e?J
20. 6ir$!b+um ;8. A4ei ei'en+rti'e :r0r+n0un' "e Aentr+lner@en2tem n+$!
Art "er p+ti$!en Peu"o0leroe (-+0ob) A 5eurol P2$!i+tr2. 192>;92:175
220. "oi: 10.1007&/P028778>1. I(ro 8e?J
21. 8i$!+r"on :P, M+ter (3. 1!e noolo'2 o? (reut<?el"t7-+0ob "ie+e +n"
$on"ition rel+te" to t!e +$$umul+tion o? PrP(-# in t!e ner@ou 2tem. /r+in
P+t!ol. 1995;5:%%>1. "oi: 10.1111&M.17507%6%9.1995.tb00575.L. IPubMe"J
I(ro 8e?J
22. #u??2 P, ;ol? -, (ollin G, #e=oe AG, *treeten /, (o4en #. Poible peron7to7
peron tr+nmiion o? (reut<?el"t7-+0ob "ie+e. 5 :n'l - Me". 197>;290:692
69%. IPubMe"J
2%. 3u'+rei :, Me"ori 8, Mont+'n+ P, /+ru<<i A, (ortelli P, 3u'+rei A, 1inuper P,
Au$$oni M, G+mbetti P. P+t+l ?+mili+l inomni+ +n" "2+utonomi+ 4it! ele$ti@e
"e'ener+tion o? t!+l+mi$ nu$lei. 5 :n'l - Me". 1986;%15:997100%. "oi:
10.1056&5:-M19861016%151605. IPubMe"J I(ro 8e?J
2>. ;ill 8G, )roni"e -;, Aei"ler M, (ouen *M, :tibeiro 6, Alpero@it$! A, Poer
*, Po$$!i+ri M, Ho?m+n A, *mit! PG. A ne4 @+ri+nt o? (reut<?el"t7-+0ob "ie+e
in t!e .6. 3+n$et. 1996;%>7:921925. "oi: 10.1016&*01>0767%6(96)91>1279.
IPubMe"J I(ro 8e?J
25. M+tri+nni -A, 5iLon 8, 3+2<er 8, 1ellin' G(, H+n #, #eArmon" *-, Pruiner
*/. Prion protein $on?orm+tion in + p+tient 4it! por+"i$ ?+t+l inomni+. 5 :n'l -
Me". 1999;%>0:16%016%8. "oi: 10.1056&5:-M19990527%>0210>. IPubMe"J
I(ro 8e?J
26. G+mbetti P, #on' A, Yu+n -, î+o ^, A!en' M, Al!e0!lee A, (+tell+ni 8,
(o!en M, /+rri+ MA, Gon<+le<78omero #, /el+2 :#, *$!onber'er 3/, M+r"er
6, H+rri (, /ur0e -8, Montine 1, ;inie40i 1, #i$0on #;, *oto (, Hulette
(M, M+tri+nni -A, 6on' O, Aou ;O. A no@el !um+n "ie+e 4it! +bnorm+l
prion protein eniti@e to prote+e. Ann 5eurol. 2008;6%:697708. "oi:
10.1002&+n+.21>20. IPM( ?ree +rti$leJ IPubMe"J I(ro 8e?J
27. Me+" *, *tump? MP, ;!it?iel" -, /e$0 -, Poulter M, (+mpbell 1, .p!ill -,
Gol"tein #, Alper MP, Pi!er :, (ollin'e -. /+l+n$in' ele$tion +t t!e prion
protein 'ene $onitent 4it! pre!itori$ 0uruli0e epi"emi$. *$ien$e.
200%;%00:6>06>%. "oi: 10.1126&$ien$e.108%%20. IPubMe"J I(ro 8e?J
28. /el+2 :#. 1r+nmiible pon'i?orm en$ep!+lop+t!ie in !um+n. Annu 8e@
Mi$robiol. 1999;5%:28%%1>. "oi: 10.11>6&+nnure@.mi$ro.5%.1.28%. IPubMe"J
I(ro 8e?J
29. /r+n"el -P. 1r+nmiible pon'i?orm en$ep!+lop+t!ie. Erp!+net :n$2$lope"i+.
200>. pp. 17.!ttp:&&444.orp!+.net&"+t+&p+t!o&G/&u071*:.p"?
%0. 6+4+u$!i Y, 6+mit+ni 1, Y+'i!it+ *, 6it+moto 1, 6i!i"+ H. Autop2 $+e o?
(reut<?el"t7-+0ob "ie+e 4it! Met&=+l !etero<2'oit2 +t $o"on 129 +n" t2pe
1prote+e7reit+nt prion protein preentin' ome ?lori"7t2pe pl+Due +n" m+n2
6uru pl+Due in t!e $erebellum. 5europ+t!olo'2. 2006;26:%1%%17. "oi:
10.1111&M.1>>071789.2006.0068%.L. IPubMe"J I(ro 8e?J
%1. (orneliu -8, /oe (-, G!e+rin' G, 3e+@itt -A, 6um+r 5. =iu+l 2mptom in
t!e Hei"en!+in @+ri+nt o? (reut<?el"t7-+0ob #ie+e. - 5euroim+'in'.
2009;19:28%287. "oi: 10.1111&M.155276569.2008.0029>.L. IPubMe"J I(ro 8e?J
%2. P+r$!i P, *tr+mmiello 8, Giee A, 6ret<$!m+r H. P!enot2pi$ @+ri+bilit2 o?
por+"i$ !um+n prion "ie+e +n" it mole$ul+r b+i: p+t, preent, +n" ?uture.
A$t+ 5europ+t!ol. 2011;121:91112. "oi: 10.1007&00>0170107077976. IPubMe"J
I(ro 8e?J
%%. (ourt 3, /ert -. :le$trop!2iolo'ie "e en$ep!+lop+t!ie tr+nmiible. P+t!
/iol. 1995;>%:25>2. IPubMe"J
%>. /r+toie4i$<7;+i0 -, 3iber0i PP, Gol+n0+ :, -+nen GH, ;+i0 1-. 8e'ul+tor2
eDuen$e o? t!e P85P 'ene in?luen$e u$eptibilit2 to por+"i$ (reut<?el"t7
-+0ob "ie+e. 5euro$i 3ett. 2007;>11:16%167. "oi:
10.1016&M.neulet.2006.08.001. IPubMe"J I(ro 8e?J
%5. Me+" *, M+!+l *P, /e$0 -, (+mpbell 1, P+rr+ll M, Pi!er :, (ollin'e -.
*por+"i$77but not @+ri+nt77(reut<?el"t7-+0ob "ie+e i +o$i+te" 4it!
pol2morp!im uptre+m o? P85P eLon 1. Am - Hum Genet. 2001;69:1225
12%5. "oi: 10.1086&%2>710. IPM( ?ree +rti$leJ IPubMe"J I(ro 8e?J
%6. P+lmer M*, #r2"en A-, Hu'!e -1, (ollin'e -. Homo<2'ou prion protein
'enot2pe pre"ipoe to por+"i$ (reut<?el"t7-+0ob "ie+e. 5+ture.
1991;%52:%>0%>2. "oi: 10.10%8&%52%>0+0. IPubMe"J I(ro 8e?J
%7. ;in"l E, #empter M, :tibeiro -P, 3+t!e 8, #e *il@+ 8, :mon"e 1, ;ill 8,
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58. Al<u+l"e A, )n"+0oetLe+ /, Perrer ), Moreno P, /+r+n"i+r+n M, Goroti"i A,
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perip!er+l p+t!olo'2 o? 0uru: p+t!olo'i$+l +n+l2i o? + re$ent $+e +n"
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66. ;+"4ort! -#P, -oiner *, 3ine!+n -M, #ebrul+i M, PoL 6, (ooper *, (ronier
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;el$! -, *tone 3, 3lo2" *:, Hill AP, /r+n"ner *, (ollin'e -. Hum+n prion
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(ollin'e -. #io$i+tion o? p+t!olo'i$+l +n" mole$ul+r p!enot2pe o? @+ri+nt
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76. ;roe *-, P+l *, *i""iDue #, H2+re H, M+$?+rl+ne 8, -oiner *, 3ine!+n -M,
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77. ;ilon 6, 8i$0ett M5. A ne4 !um+n 'enot2pe prone to @+ri+nt (reut<?el"t7
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78. 6+0i #, Me+" *, H2+re H, (ooper *, -+mp+n+ 8, E@erell -, 6ni'!t 8, (ollin'e
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79. /ro4n P, Pree$e M, /r+n"el -P, *+to 1, M$*!+ne 3, Aerr ), Plet$!er A, ;ill 8G,
Po$$!i+ri, (+!m+n 58, "NAi'n+uL -H, (er@en+N0o@+N 3, Pr+"0in -, *$!onber'er
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5-, #i$0on #, Honi' 3, 1orre -M, M+tri+nni -, (+pell+ri *, Gi+$$one G, /el+2
:#, *$!onber'er 3/, (o!en M, Perr2 G, 6on' O, P+r$!i P, 1+'li+@ini P,
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82. 8o"rh'ue<7M+rthne< A/, G+rri"o -M, A+rr+n< --, Arte+'oiti+ -M, "e P+n$orbo
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Jurnal @
*olecular-Imaging Probe 6-<1-AB-C<6-
3luoroethyl=<*ethyl= AminoD-6-
NaphthylE%thylidene= *alononitrile
'abels Prion Pla9ues In Vitro
1. M+r+ /reM+n+$ 1,2,
2. 3oM<e M. *mi" 1,2,
%. 1om+< #. =o@0o 1,2,
>. An"reM Petrij %,
5. -or'e 8. /+rrio >, +n"
6. M+r+ Popo@i$ 2
[ Aut!or A??ili+tion
1.
1
L'-or'$or/ or N&*ron'! P!'%$"#"$/ 'n0 R&1&n&r'$"on2 In%$"$*$& o
P'$3op3/%"o!o1/2
2
Pr"on L'-or'$or/2 In%$"$*$& o P'$3o!o1/2 S#3oo! o M&0"#"n&2
'n0
3
4'#*!$/ o C3&("%$r/ 'n0 C3&("#'! T&#3no!o1/2 Un".&r%"$/ o L5*-!5'n'2 SI6
1777 L5*-!5'n'2 S!o.&n"'2 'n0
8
D"."%"on o N*#!&'r M&0"#"n&2 D&p'r$(&n$ o
Mo!&#*!'r 'n0 M&0"#'! P3'r('#o!o1/2 L'-or'$or/ o S$r*#$*r'! B"o!o1/ 'n0
Mo!&#*!'r M&0"#"n&2 Un".&r%"$/ o C'!"orn"'2 Lo% An1&!&%2 S#3oo! o M&0"#"n&2
Lo% An1&!&%2 C'!"orn"' 97799

5eLt *e$tion
Abstract
1!e tu"2 +ime" to e@+lu+te t!e ?luore$ent mole$ul+r7im+'in' probe 27(17k67I(27
?luoroet!2l)(met!2l)+minoJ727n+p!t!2llet!2li"ene)m+lononitrile (P##5P) ?or it +bilit2
to ele$ti@el2 +n" repro"u$ibl2 l+bel prion pl+Due in ?iLe", p+r+??in7embe""e" $erebell+r
e$tion ?rom p+tient o? $on?irme" Gertm+nn7*trùler7*$!ein0er "ie+e, por+"i$
(reut<?el"t7-+$ob "ie+e ((-#) 4it! 0uru pl+Due, +n" @+ri+nt (-# (@(-#). P##5P i +
!i'!l2 !2"rop!obi$, @i$oit27eniti@e, ol@ent7eniti@e, ?luore$ent ubt+n$e, 4!oe
r+"io?luorin+te" +n+lo' I
18
PJP##5P !+ re$entl2 been u$$e?ull2 ue" to l+bel enile
pl+Due +n" neuro?ibrill+r2 t+n'le in t!e li@in' br+in o? Al<!eimerN "ie+e p+tient 4it!
poitron emiion tomo'r+p!2. Eur reult !o4 t!+t P##5P reli+bl2 i"enti?ie +ll prion
pl+Due, in$lu"in' m+ll $luter7pl+Due in @(-#. 1!i ?in"in' m+2 open ne4 "n .".o
"i+'noti$ poibilitie ?or @(-#.
fluorescent labeling
human
neuroimaging
T&%
7ariant $reut-feldt-Jacob disease
amyloid
Pre@iou *e$tion 5eLt *e$tion
Introduction
1r+nmiible pon'i?orm en$ep!+lop+t!ie (1*:), +lo 0no4n + prion "ie+e, +re +
'roup o? in@+ri+bl2 ?+t+l neuro"e'ener+ti@e "ior"er t!+t +??e$t bot! !um+n +n" +nim+l
(Pruiner, 1998). #epite t!eir r+rit2 ( 1 $+e per million per 2e+r), !um+n 1*: !+@e +
"r+m+ti$ imp+$t be$+ue o? t!eir $lini$+l pro?ile +n" $omplete +ben$e o? e??e$ti@e
tre+tment. (on$ern o? poible tr+nmiion o? prion "ie+e t!rou'! ur'i$+l +n"
"ent+l pro$e"ure, tiue tr+npl+nt+tion, +n" bloo" tr+n?uion !+@e been ?uele" b2 +
re$ent emer'en$e o? + ne4 @+ri+nt (reut<?el"t7-+$ob "ie+e (@(-#) (;ill et +l., 1996)
+n" e@i"en$e o? it +o$i+tion 4it! t!e epi"emi$ o? bo@ine pon'i?orm en$ep!+lop+t!2.
#e?initi@e "i+'noi o? + prion "ie+e reDuire + potmortem p+t!omorp!olo'i$+l
inpe$tion o? t!e br+in, 4!i$! i uu+ll2 $ombine" 4it! immunolo'i$+l "ete$tion +n"
$!+r+$teri<+tion o? t!e p+t!olo'i$+l prion protein PrP
*$
(#eArmon" et +l., 2002). 1!ere
+re $urrentl2 + ?e4 +ntemortem in@eti'+tion t!+t $+n $onoli"+te + $lini$+l upi$ion o?
+ prion "ie+e (e.'., ::G, m+'neti$ reon+n$e br+in im+'in', immuno++2 ?or + r+n'e
o? nonpe$i?i$ m+r0er). 5one o? t!em, !o4e@er, !+ +n i"e+l eniti@it2 +n" pe$i?i$it2
pro?ile. )n p+rti$ul+r, t!ee in@eti'+ti@e te$!niDue "o not +ppe+r to be "e$ii@e in
e$urin' t!e "i+'noi o? @(-#. 1!ere?ore, in@+i@e pro$e"ure (i.e., (5* or
l2mp!oreti$ul+r tiue biop2) !+@e been ue" to $on?irm t!e preen$e o? PrP
*$
in
upe$te" @(-# ()roni"e et +l., 2002).
8e$entl2, /+rrio et +l. (1999) "e@elope" 27(17k67I(27I
18
PJ?luoroet!2l) (met!2l)+minoJ727
n+p!t!2llet!2li"ene)m+lononitrile (I
18
PJP##5P; I
18
PJ, $1&2 F 110 min) ?or poitron
emiion tomo'r+p!2 (P:1) $+n "ete$tion o? +m2loi" "epoit in Al<!eimerN "ie+e
(A'"epp+ et +l., 2001). More re$entl2, + mo"i?ie" @erion o? t!io?l+@in71 l+bele" 4it!
11
(
($1&2 F 20 min) 4+ +lo intro"u$e" 4it! imil+r intent (/+$0+i et +l., 2002). I
18
PJP##5P
$roe t!e bloo"7br+in b+rrier +n" re@e+l t!e lo$+li<+tion +n" lo+" o? enile pl+Due +n"
neuro?ibrill+r2 t+n'le in t!e li@in' br+in o? Al<!eimerN "ie+e p+tient (A'"epp+ et +l.,
2001; *!o'!i7-+"i" et +l., 2002). A P:1 mole$ul+r im+'in' probe t!+t $oul" imil+rl2
re@e+l prion pl+Due 4oul" be p+rti$ul+rl2 rele@+nt ?or t!e "i+'noi o? @(-#, in 4!i$!
m+i@e prion pl+Due +re + !+llm+r0 o? t!e "ie+e +n" !+@e + $!+r+$teriti$ "itribution
4it!in t!e (5* (;ill et +l., 1996; Aei"ler et +l., 1997; #eArmon" et +l., 2002; )roni"e et
+l., 2002).
P##5P i + !2"rop!obi$ ubt+n$e t!+t bin" to it li'+n" t!rou'! !2"rop!obi$
inter+$tion (A'"epp+ et +l., 2001). )t $+n be eL$ite" in t!e @iible p+rt o? t!e pe$trum
bet4een >>0 +n" >90 nm. )t ?luore$ent emiion i en@ironment+ll2 eniti@e, bein'
poorl2 ?luore$ent in 4+ter +n" o? $oni"er+bl2 tron'er ?luore$en$e 4!en in @i$ou
en@ironment, or 4!en boun" (-+$obon et +l., 1996; Petri$ et +l., 1998; A'"epp+ et +l.,
2001; *!o'!i7-+"i" et +l., 2002). Am(17>0) ?ibril7boun" P##5P pe+0 emiion i +t
500 nm ( A'"epp+ et +l., 2001).
1!e +im o? t!i tu"2 4+ to ue t!e nonr+"io+$ti@e P##5P +n" "etermine it "n ."$ro
potenti+l ?or pl+Due l+belin' in !um+n prion "ie+e 4it! +m2loi" pl+Due, 4it!
p+rti$ul+r emp!+i on @(-#.
*aterials and *ethods
*e$tion o? p+r+?orm+l"e!2"e7?iLe", p+r+??in7embe""e" !um+n $erebell+r +mple ?rom
p+tient 4it! $on?irme" por+"i$ (-# ((-#) 4it! 0uru pl+Due, Gertm+nn7*trùler7
*$!ein0er (G**) 2n"rome (4it! t!e P1023 mut+tion o? t!e PRNP 'ene; 'eneroul2
pro@i"e" b2 #r. Herbert /u"0+, )ntitute o? 5eurolo'2, .ni@erit2 o? =ienn+, +n"
Autri+n 8e?eren$e (entre ?or Hum+n Prion #ie+e, =ienn+, Autri+; H+in?ellner +t +l.,
1995), +n" @(-# ('eneroul2 pro@i"e" b2 #r. -+me )roni"e, 5europ+t!olo'2
3+bor+tor2, (-# *ur@eill+n$e .nit, .ni@erit2 o? :"inbur'!, :"inbur'!, .6) 4ere ue"
in t!e tu"2. )n +""ition, tiue e$tion o? eDu+ll2 pro$ee" br+in o? + "e$e+e"
in"i@i"u+l (norm+l $ontrol) 0no4n not to !+@e !+" + prion "ie+e or +n2 ot!er
neurolo'i$+l "ior"er 4+ ue" + + ne'+ti@e $ontrol. 1!e (-# +n" @(-# (but not G** or
norm+l) $erebell+r +mple 4ere immere" in 96U ?ormi$ +$i" ?or 1 !r +?ter ?iL+tion in
p+r+?orm+l"e!2"e.
1!e 57bm7t!i$0 e$tion 4ere eit!er ue" imme"i+tel2 +?ter "ep+r+??in+tion or +?ter
+nti'en retrie@+l pro$e"ure in@ol@in' %0 min +uto$l+@in' +t 121n( in "itille" 4+ter +n"
ubeDuent 5 min in$ub+tion in 96U ?ormi$ +$i", 4!i$! i t!e t+n"+r" re$ommen"e"
pretre+tment ?or PrP
*$
immuno"ete$tion in tiue +mple (He'2i et +l., 1997).
Mono$lon+l +ntibo"2 (MAb) %P> 4+ ue" (#+0o, Glotrup, #enm+r0) ?or
immuno?luore$ent ()P) +n" immuno!ito$!emi$+l ()H() "ete$tion o? PrP
*$
. /ot!
immuno"ete$tion pro$e"ure 4ere in"ire$t, uin' biotin2l+te" e$on"+r2 +ntibo"2 +n"
trept+@i"in7?luorop!ore $onMu'+te ()P) or +@i"in7biotin7peroLi"+e 4it! %_,%7
"i+minoben<i"ine ()H(). /rie?l2, t!e e$tion 4ere rine" in bu??er be?ore + >U norm+l
!ore erum 4+ +pplie" in bu??er, pH 7.2, ?or 20 min to blo$0 t!e nonpe$i?i$ bin"in' o?
t!e e$on"+r2 +ntibo"2. )n$ub+tion 4it! t!e prim+r2 +nti7PrP MAb %P> (%710 b'&ml) 4+
per?orme" o@erni'!t +t >n(. )n$ub+tion in t!e biotin2l+te" !ore +nti7moue e$on"+r2
+ntibo"2 (1:1000; =e$tor 3+bor+torie, /urlin'+me, (A) 4+ ?ollo4e" b2 in$ub+tion in
t!e +@i"in7biotin7peroLi"+e $ompleL (A/( *t+n"+r" :lite 6it; =e$tor 3+bor+torie) +n"
$!romo'en (%_,%7"i+minoben<i"ine; *i'm+, #eien!o?en, Germ+n2) olution, or
trept+@i"in7AleL+ >88 (Mole$ul+r Probe, :u'ene, E8). )n )H(, !em+toLilin
$ountert+inin' 4+ ue" to @iu+li<e t!e $ell nu$lei.
P##5P 4+ 2nt!ei<e" + "e$ribe" pre@ioul2 (A'"epp+ et +l., 2001). 3+belin' 4+
per?orme" on "ep+r+??in+te" e$tion t+ine" 4it! !em+toLilin, rine" in 4+ter, +n"
immere" ?or 5 min in 1U *u"+n bl+$0 olution in 70U et!+nol to re"u$e t!e
+uto?luore$en$e o? lipo?u$in (*$!nell et +l., 1999) +n" ot!er tiue $omponent.
*e$tion 4ere rine" 4it! 4+ter, +n" eL$e *u"+n bl+$0 4+ remo@e" b2 "ippin' t!e
li"e in 70U et!+nol. 1!e e$tion 4ere t!en in$ub+te" 4it! + ?re!l2 prep+re" 10 bm
P##5P in +Dueou 1U et!+nol (@&@) in t!e "+r0 +t room temper+ture (A'"epp+ et +l.,
2001). 1!e t+ine" tiue 4+ rine" 4it! 4+ter +n" $o@erlippe" 4it! 'l2$erol be?ore
@ie4in' un"er t!e ?luore$ent mi$ro$ope.
3+belin' o? t!e +me pl+Due 4it! P##5P +n" %P> immuno?luore$en$e 4+ per?orme"
in eDuen$e, +n" t!e P##5P 4+ +pplie" ?irt to + ?re!l2 "ep+r+??in+te" e$tion. 1!e
t+ine" e$tion 4+ p!oto'r+p!e", rine" in et!+nol to remo@e P##5P, +n" pretre+te" ?or
immuno"ete$tion o? PrP
*$
+''re'+te, + "e$ribe" +bo@e. /e?ore +ppl2in' %P> to t!ee
e$tion, 4e @eri?ie" t!+t no rem+inin' P##5P ?luore$en$e 4+ "ete$te" in t!e pl+Due.
)n t!e ?in+l erie, e$tion 4ere ?irt t+ine" 4it! P##5P, p!oto'r+p!e", rine" in
et!+nol, +n" t+ine" 4it! perio"i$ +$i"7*$!i?? (PA*). PA* 4+ $!oen o@er t!e more
+m2loi"7pe$i?i$ (on'o re" t+inin' be$+ue o? t!e better l+belin' pro?ile o? m+ller
pl+Due 4it! t!e ?ormer "2e. A?ter $olle$tion o? p!oto'r+p! o? t!e PA*7t+ine" pl+Due,
4e eLpoe" t!e +me e$tion to t!e +nti'en retrie@+l proto$ol +n" pro$ee" t!em ?or
)H( "ete$tion o? PrP
*$
4it! %P>.
P!otomi$ro'r+p! 4ere t+0en on + 5i0on :$lipe :600 li'!t +n" ?luore$ent mi$ro$ope
eDuippe" 4it! +ppropri+te ?ilter (:^ >657695, #M 505, /A 5157555), 4it! + 5i0on
#^M 1200 "i'it+l $+mer+, +n" $onne$te" to + peron+l $omputer im+'e +n+l2i t+tion.
M()# )m+'e An+l2i *2tem o?t4+re ()m+'e An+l2i *2tem, *t. (+t!+rine, Ent+rio,
(+n+"+) 4+ ue" to i"enti?2 in"i@i"u+l pl+Due, to @eri?2 t!eir l+belin' 4it! "i??erent
te$!niDue, +n" to "etermine t!e i'n+l ur?+$e +re+ in P##5P7, PA*7, +n" %P>7)H(7
l+bele" e$tion. /rie?l2, + mi$ro$opi$ im+'e 4+ "i'iti<e", +n" + i'n+l t!re!ol" 4+
"etermine" ?or e+$! o? t!e l+belin' met!o" +pplie" to t!e +me lo$i (n F > ?iel" +t 200G
m+'ni?i$+tion). 1!e i'n+l ur?+$e +re+ 4+ t!en me+ure", +n" P##5P +n" PA* reult
4ere eLpree" + per$ent+'e (+@er+'e S *#) o? t!e %P>7)H( me+urement reult. Pin+l
im+'e 4ere $re+te" b2 peu"o$olorin' t!e ori'in+l 'reen ?luore$ent i'n+l 2ello4 in
+$$or"+n$e 4it! t!e reDuirement ?or "i'it+l +rt prep+r+tion.
esults
3""NP identifies typical prion pla9ues in human prion diseases
*t+n"+r" )H( re@e+le" "i@ere prion +''re'+te in t!e $erebell+r tiue e$tion ?rom +ll
t!e prion "ie+e $+e ue" in t!i tu"2: + 0uru pl+Due in (-# (Pi'. 1 '), multi$entri$
pl+Due in G** (Pi'. 1 #), +n" t2pi$+l pi0e"7b+ll pl+Due in @(-# (Pi'. 1 &). )n +"M+$ent
e$tion, "i??erent prion pl+Due 4ere $onitentl2 +n" intenel2 l+bele" 4it! P##5P in
t!e +me p+ttern $!+r+$teriti$ ?or e+$! o? t!e t!ree prion "ie+e (Pi'. 1 -2 0 , +n" ,
repe$ti@el2). A imult+neoul2 pro$ee" e$tion ?rom + norm+l $erebellum (Pi'. 1 16")
"ipl+2e" no "ete$t+ble ?luore$ent l+belin' 4it! P##5P (Pi'. 1 5).
=ie4 l+r'er @erion:
)n t!i p+'e
)n + ne4 4in"o4
#o4nlo+" + Po4erPoint *li"e
Pi'ure 1.
'2 -, (omp+rion o? t+n"+r" immuno!ito$!emitr2 +n" P##5P pl+Due l+belin'. )H(
4it! %P> MAb re@e+l t2pi$+l prion +''re'+te in t!e $erebell+r tiue e$tion ?rom +ll
t!e prion "ie+e $+e ue" in t!i tu"2: 0uru pl+Due in (-# ('), multi$entri$ pl+Due
in G** (-), +n" t2pi$+l pi0e"7b+ll pl+Due in @(-# (#). #i??erent prion pl+Due !o4
intene l+belin' 4it! P##5P in t!e +me 'ener+l p+ttern $!+r+$teriti$ ?or e+$! o? t!e
t!ree prion "ie+e (06, repe$ti@el2). 175, 5orm+l $ontrol $erebell+r e$tion t+ine" onl2
4it! !em+toLilin (1) "ipl+2 $oni"er+ble +uto?luore$en$e (3) t!+t 4+ Duen$!e" b2
*u"+n bl+$0 t+inin' ("2 5). )n +""ition, +ben$e o? ?luore$ent i'n+l +?ter P##5P
l+belin' o? t!e +me e$tion i !o4n in 5. Green ?luore$ent i'n+l 4+ peu"o$olore"
2ello4. *$+le b+r: '7, 50 bm; 175, 15 bm.
3""NP pla9ue identification is confirmed by prion-specific
immunolabeling
*eDuenti+l +ppli$+tion o? prion immunol+belin' +n" P##5P to t!e +me tiue e$tion
permitte" + "ire$t $ontrol o? prion pl+Due "ete$tion +n" l+belin' 4it! P##5P. Aben$e o?
+nti'en retrie@+l te$!niDue pre$lu"e u$$e?ul immuno"ete$tion o? mot prion
+''re'+te 4it! +nti7PrP +ntibo"ie on ?orm+l"e!2"e7?iLe", p+r+??in7embe""e" tiue
e$tion. 1!u, !+r! +nti'en retrie@+l !+ to be ue" to +llo4 optim+l immuno"ete$tion
o? prion +''re'+te (He'2i et +l., 1997). *u$! tiue pretre+tment 4+ "etermine" not to
be $omp+tible 4it! P##5P pl+Due l+belin' ("+t+ not !o4n). 1!ere?ore, P##5P 4+
+pplie" ?irt onto ?re!l2 "ep+r+??in+te" e$tion +n" ?oun" to ele$ti@el2 +n"
repro"u$ibl2 l+bel prion pl+Due o? @+riou i<e, in$lu"in' m+ller $luter7pl+Due in
@(-# $erebell+r e$tion (Pi'. 2 '). P##5P bin"in' i re@erible, +n" no pl+Due
?luore$en$e $oul" be "ete$te" +?ter e@er+l et!+nol rine Mut be?ore %P> MAb
+ppli$+tion to t!e +me e$tion (Pi'. 2 -). )P "ete$tion o? prion +''re'+te 4it! %P> +t t!e
+me lo$+tion pre@ioul2 l+bele" 4it! P##5P re@e+le" + Du+lit+ti@el2 @er2 imil+r
pi$ture: intenel2 l+bele" l+r'e pl+Due +n" numerou m+ller, le intenel2 l+bele"
$luter7pl+Due (Pi'. 2 #). All o? t!e )P7l+bele" pl+Due (Pi'. 2 #2&) $+n be i"enti?ie" in t!e
P##5P7l+bele" e$tion (Pi'. 2 '20). Ou+ntit+ti@el2, !o4e@er, t!ere 4+ + "i??eren$e in
prion "epoit @iu+li<+tion 4it! P##5P (Pi'. 2 0), +n" %P> immuno?luore$en$e (Pi'. 2 &)
in ?+@or o? t!e immuno"ete$tion met!o", 4!i$! "epen" on @er2 e??e$ti@e i'n+l
+mpli?i$+tion.
=ie4 l+r'er @erion:
)n t!i p+'e
)n + ne4 4in"o4
Pi'ure 2.
(omp+rion o? P##5P prion pl+Due l+belin' 4it! )P "ete$tion o? prion in t!e +me
e$tion o? @(-# $erebellum. P##5P tron'l2 l+bele" l+r'e pl+Due (', +rro4). Ho4e@er,
m+ller $luter7pl+Due (', +rro4!e+") $oul" +lo be "i$erne" +'+int t!e tiue
b+$0'roun". 1!e +me pl+Due "ipl+2e" no rei"u+l ?luore$en$e +?ter et!+nol rinin' to
remo@e P##5P (-, +rro4 +n" +rro4!e+"). A?ter +nti'en retrie@+l, %P> MAb bin"in'
@iu+li<e" b2 in"ire$t immuno?luore$en$e 4it! AleL+ >88 re@e+le" prion +''re'+te in
t!e +me +re+ (#), !o4in' t!e +me l+belin' p+ttern + P##5P (#, +rro4 +n" +rro4!e+")
but + tron'er, +mpli?ie" ?luore$en$e o? t!e m+ller +''re'+te. A !i'!er7m+'ni?i$+tion
@ie4 o? +not!er $luter o? @(-# $erebell+r pl+Due l+bele" 4it! P##5P (0) +n"
ubeDuentl2 4it! %P>7)P (&) +llo4 better ini'!t into "et+il o? pl+Due l+belin' 4it! t!e
t4o met!o" (?or $omp+rion, t!e +me m+ll pl+Due in 0 +n" & i in"i$+te" b2 +n
+rro4!e+"). All ?luore$ent im+'e 4ere peu"o$olore". *$+le b+r: '6#, 200 bm; 02 &, 50
bm.
&mall cluster-pla9ues in 7$J" cerebellum are readily detected by 3""NP
but not PA&
*eDuenti+l l+belin' o? t!e +me e$tion 4it! P##5P (Pi'. % '), PA* (Pi'. % -), +n"
e@entu+ll2 4it! pe$i?i$ +nti7PrP MAb %P>7)H( (Pi'. % #) permitte" + rou'! $omp+rion
o? t!e eLtent o? t!e +me prion pl+Due l+belin' 4it! t!e t!ree met!o". Alt!ou'! t!e
t+n"+r" )H( 4it! intene i'n+l +mpli?i$+tion +n" $!romo'en pre$ipit+tion pro@e"
uperior to bot! nonpe$i?i$ met!o", P##5P !o4e" +n +pp+rent +"@+nt+'e o@er PA*
in @iu+li<in' t!e m+ll $luter7pl+Due in t!e $erebellum.
=ie4 l+r'er @erion:
)n t!i p+'e
)n + ne4 4in"o4
Pi'ure %.
(omp+rion o? $one$uti@e l+belin' o? t!e +me lo$u o? + in'le tiue e$tion 4it!
P##5P (', 2ello4 peu"o$olore" pl+Due), PA* (-, m+'ent+7l+bele" pl+Due), +n" )H(
to PrP
*$
(#, bro4n pre$ipit+te). P##5P l+bele" bot! l+r'er +m2loi" +n" m+ller $luter7
pl+Due, 4!ere+ PA* re+"il2 i"enti?ie motl2 l+r'er +m2loi" pl+Due. :??e$ti@e +nti'en
retrie@+l +n" i'n+l +mpli?i$+tion o? prion immunol+belin' 4it! +nti7PrP MAb +llo4
@iu+li<+tion o? +ll prion "epoit o@er + 4i"e +re+ in t!e +me lo$+tion. *$+le b+r, 200
bm.
1!e "i??eren$e bet4een pl+Due l+belin' te$!niDue @iible in Pi'ure 2 +n" % 4ere
rou'!l2 Du+nti?ie" b2 eLprein' P##5P7 +n" PA*7l+bele" ur?+$e +re+ + per$ent+'e o?
t!e ur?+$e +re+ o? t!e +me tiue e$tion l+bele" 4it! %P>7)H(: P##5P i'n+l ur?+$e
+re+ 4+ 16 S >U, 4!ere+ PA* i'n+l ur?+$e +re+ $o@ere" 6 S 2U o? t!e ur?+$e +re+
l+bele" 4it! %P>7)H(.
"iscussion
1!i tu"2 +ime" to e@+lu+te t!e ?luore$ent mole$ul+r probe P##5P ?or it +bilit2 to
ele$ti@el2 +n" repro"u$ibl2 l+bel prion pl+Due in ?iLe", p+r+??in7embe""e" $erebell+r
e$tion ?rom p+tient o? $on?irme" G**, (-# 4it! 0uru pl+Due, +n" @(-#. Eur reult
!o4 t!+t P##5P reli+bl2 i"enti?ie prion pl+Due in +ll tiue +mple. )t +bilit2 to
ele$ti@el2 "ete$t prion pl+Due o? @+riou i<e in t!e tete" tiue +mple 4+
$on?irme" b2 )P i"enti?i$+tion o? t!e +me pl+Due 4it! + t+n"+r" +nti7PrP +ntibo"2,
%P>. )n @(-# +mple, P##5P +llo4e" "ete$tion o? m+ller pl+Due better t!+n PA*
t+inin' o? t!e +me prion +''re'+te, 4!i$! 4+ $on?irme" b2 ubeDuent )H( "ete$tion
o? t!e ?ull eLtent o? PrP
*$
"epoit +t t!e +me lo$u o? in"i@i"u+l tiue e$tion.
Amyloid pla9ues in prion diseases
1!e oprotein onl2p !2pot!ei t+te t!+t t!e in?e$tiou +'ent $+uin' 1*: i +
$on?orm+tion+l iomer o? PrP
(
, + !ot protein, t!e ?un$tion o? 4!i$! i till poorl2
un"ertoo" (Pruiner, 1998). 1!e p+t!olo'i$+l iomer, PrP
*$
, !+ !i'! m7!eet $ontent, i
l+r'el2 prote+e7reit+nt, +n" ?orm +''re'+te, 4!i$! +$$umul+te in t!e br+in (Pruiner,
1998). #i??erent t2pe o? prion +''re'+te +n" t!eir +n+tomi$+l "itribution +re
$!+r+$teriti$ ?or "i??erent prion "ie+e (#eArmon" et +l., 2002). Alt!ou'! prion
"epoit $+n be o? @+riou i<e +n" tru$ture, prion ?reDuentl2 ?orm +m2loi" pl+Due,
4!i$! +re + !+llm+r0 o? ome prion "ie+e u$! + G**, (-# 4it! 0uru pl+Due, +n"
@(-# (#eArmon" et +l., 2002). 1!e l+tter "ie+e i + prime $+n"i"+te $on"ition ?or
nonin@+i@e "n .".o pro$e"ure, 4!i$! 4oul" +i" "i+'noi.
&uspected 7$J"4 a diagnostic challenge
(urrentl2, t!e $lini$+l $oure i 0e2 to et+bli!in' + 4or0in' "i+'noi o? @(-#.
:motion+l +n" be!+@ior+l $!+n'e o$$ur e+rl2 in @(-# +n" ?reDuentl2 in@ol@e "epreion
or p2$!oi. 1!e l+$0 o? m+r0e" or'+ni$ ?e+ture o?ten le+" to + p2$!i+tri$ "i+'noi
(Aei"ler et +l., 1997). 1!e upi$ion o? @(-# i r+ie" i? +t+Li+ +n" ?or'et?ulne "e@elop
(Aei"ler et +l., 1997). #i+'noi o? @(-# m+2 be $on?irme" b2 "ete$tin' PrP
*$
in biop2
pe$imen, but t!e nonuni?orm tiue "itribution o? t2pi$+l o?lori"p pl+Due in t!e (5*
+n" lo4 $on$entr+tion o? PrP
*$
in l2mp!oreti$ul+r tiue !+ o$$+ion+ll2 reulte" in
ne'+ti@e biop2 reult ()roni"e et +l., 2002). 1!u, "e?initi@e "i+'noi reDuire +
potmortem "ete$tion o? e@ere pon'i?orm $!+n'e in t!e b++l '+n'li+, t!+l+mu, +n"
$erebellum, + 4ell + t!e preen$e o? prion pl+Due.
1!e mot rem+r0+ble ?e+ture o? @(-# i t!e obli'+tor2 m+i@e +mount o? prion +m2loi"
pl+Due, m+n2 4it! ?e+ture o? 0uru pl+Due, +n" t!e !u'e number o? primiti@e pl+Due7
li0e "epoit t!+t +re PA* nonre+$ti@e (#eArmon" et +l., 2002). All re'ion o? t!e
$erebr+l $orteL $ont+in prion pl+Due, but t!e !i'!et $on$entr+tion o$$ur in t!e
$erebellum (#eArmon" et +l., 2002; )roni"e et +l., 2002). 1!ere?ore, + P:1 $+n probe,
4!i$! 4oul" reli+bl2 +n" eniti@el2 l+bel prion pl+Due in br+in o? li@in' p+tient,
4oul" be o? 're+t potenti+l @+lue.
Potential for molecular-imaging of amyloid pla9ues with C
1F
3D3""NP-P%T
in vivo
A mole$ul+r probe u$! + P##5P t!+t bin" to +m2loi" pl+Due 4it! !i'! +??init2
(A'"epp+ et +l., 2001; *!o'!i7-+"i" et +l., 2002) i li0el2 to meet t!e reDuirement o?
u??i$ient eniti@it2. P##5P i + !2"rop!obi$ mole$ule t!+t ?orm in"u$e" "ipole
bet4een t!e "onor 'roup (e.'., "i+l02l +mino) +n" +$$eptor moiet2 (e.'., m+lononitrile) in
@+riou en@ironment+l $on"ition. ;e !2pot!ei<e t!+t t!ee "ipole 4oul" ?orm
!2"ro'en bon" inter+$tion 4it! 'roup on t!e !2"rop!obi$ ur?+$e o? m7+m2loi"
+''re'+te (or t+u +''re'+te in neuro?ibrill+r2 t+n'le), 'i@in' rie to t!e uniDue bin"in'
propertie o? t!i ne4 probe. P##5P i not t!e onl2 mole$ul+r probe t!+t !+ been
"e@elope" ?or t!e purpoe o? "n .".o neuroim+'in' o? +m2loi" pl+Due (/+$0+i et +l.,
2002; 6un' et +l., 2002). Ho4e@er, I
18
PJP##5P it i t!e onl2 ubt+n$e t!+t !+" been
u$$e?ull2 ue" to lo$+li<e +n" +e t!e bur"en o? enile pl+Due +n" neuro?ibrill+r2
t+n'le in li@in' br+in o? Al<!eimerN p+tient.
1!e l+$0 o? pe$i?i$it2 o? P##5P ?or prion pl+Due o@er +m2loi" pl+Due o? Al<!eimerN
"ie+e, or ot!er +m2loi" "epoit in t!e br+in, mi'!t be @ie4e" + +n +pp+rent
"i+"@+nt+'e. Ho4e@er, +n in"i$+tion ?or + pl+Due7"ete$tin' P:1 $+n in + $+n"i"+te
@(-# p+tient 4oul" be b+e" on + t!orou'! $lini$+l e@+lu+tion +n" p+tient !itor2, t!u
$oni"er+bl2 re"u$in' t!e li0eli!oo" o? $on?uin' @(-# 4it! ot!er "ie+e 4it! +m2loi"
"epoition in t!e br+in, u$! + Al<!eimerN "ie+e. Purt!ermore, + prepon"er+n$e o?
pl+Due lo+" in t!e $erebellum 4oul" "itin'ui! t!e P:1 $+n reult o? + @(-# p+tient
?rom @irtu+ll2 +ll "i??erenti+l "i+'noe.
3""NP labels all ;3@-identified prion pla9ues in vitro
)n our tu"2, P##5P 4+ $omp+re" 4it! one o? t!e routine !itolo'i$+l met!o" ?or
+m2loi" t+inin', PA* (#eArmon" +t +l., 2002). ;!en +pplie" to + e$tion o? @(-#
$erebell+r tiue, P##5P 4+ !o4n to l+bel not onl2 l+r'e +m2loi" pl+Due but +lo
m+ll $luter7pl+Due t!+t 4ere not reli+bl2 @iu+li<e" 4it! ubeDuent +ppli$+tion o?
PA* onto t!e +me e$tion. )t !+ been !o4n pre@ioul2 t!+t $ert+in pl+Due, in
p+rti$ul+r t!e m+ller $luter7pl+Due repreentin' + i'ni?i$+nt proportion o? pl+Due lo+"
in @(-#, "o not "ipl+2 t2pi$+l tin$tori+l propertie o? +m2loi" (e.'., t!e2 +re not
eoinop!2li$ or PA* re+$ti@e) (#eArmon" +t +l., 2002).
1!ere?ore, in +""ition to $omp+rin' P##5P 4it! PA*, 4e +lo tete" t!e +bilit2 o?
P##5P to i"enti?2 pl+Due +'+int optimi<e" immuno"ete$tion o? prion "epoit b2 +
t+n"+r" +nti7PrP MAb, %P>. 1!e intent 4+ to obt+in + rou'! Du+ntit+ti@e +ement o?
t!e proportion o? +ll prion "epoit t!+t $+n be "ete$te" b2 P##5P. Eur reult $le+rl2
!o4 t!+t P##5P l+bele" +ll pl+Due t!+t 4ere ubeDuentl2 i"enti?ie" b2 +mpli?ie"
immuno?luore$en$e o? t!e +nti7PrP +ntibo"2 bin"in'. 1!e ober@e" "i??eren$e in t!e
intenit2 o? l+belin' b2 P##5P +n" %P> immuno?luore$en$e !oul" be interprete" in
t!e $onteLt o? t!e "i??eren$e in t!e i'n+l +mpli?i$+tion bet4een t!e t4o met!o". .e o?
PrP7pe$i?i$ +ntibo"ie on +"eDu+tel2 prep+re" tiue +n" +ppropri+te i'n+l
+mpli?i$+tion te$!niDue +llo4 @iu+li<+tion o? mot, e@en t!e ?inet (e.'., 2n+pti$) prion
"epoit. )n $ontr+t, P##5P !oul" be eLpe$te" to +$$umul+te pre"omin+ntl2 in t!oe
pl+Due 4it! +m2loi" ultr+tru$ture. =iu+li<+tion o? m+ll PA*7non"ete$t+ble pl+Due
4it! P##5P (ubeDuentl2 $on?irme" 4it! %P> bin"in') re@e+l + ?+@or+ble prion pl+Due
l+belin' pro?ile o? P##5P.
Prion "ete$tion 4it! %P> immuno?luore$en$e +n" P##5P 4ere bot! ome4!+t limite"
b2 t!e +uto?luore$ent b+$0'roun" o? +l"e!2"e7?iLe" tiue, 4!i$! reDuire" Duen$!in'
(*$!nell et +l., 1999). Ho4e@er, + le t!+n i"e+l i'n+l7to7noie r+tio +ttribut+ble to tiue
+uto?luore$en$e i +n +rti?+$t o? t!e "n ."$ro $on"ition un"er 4!i$! P##5P 4+ tete"
in t!i tu"2. 8+"iol+bele" P##5P ue" + + P:1 probe 4oul" not be li0el2 to en$ounter
t!ee problem. 1!e l+tter t+tement $oul" be tete" "n ."$ro b2 "eterminin' t!e
pe$i?i$it2 +n" eniti@it2 o? prion +m2loi" +''re'+te "ete$tion b2 + r+"iol+bele"
P##5P. )n +""ition, tr+n'eni$ mi$e (*$ott et +l., 1999) or prim+te (3+me<+ et +l.,
2001) ino$ul+te" 4it! @(-# !oul" be ue" to tet t!e I
18
PJP##5P P:1 $+n "ete$tion o?
prion pl+Due "n .".o. Pin+ll2, t!e preent e@i"en$e o? tron' "n ."$ro prion pl+Due l+belin'
4it! P##5P $ouple" 4it! t!e "o$umente" u$$e?ul +n" +?e ue o? I
18
PJP##5P to
"ete$t pl+Due lo+" in li@in' Al<!eimerN "ie+e p+tient (*!o'!i7-+"i" et +l., 2002) $oul"
timul+te prep+r+tion ?or t!e ?irt I
18
PJP##5P P:1 $+n o? $on?irme" +n" upe$te"
@(-# p+tient.
3ootnotes
o 8e$ei@e" April 8, 200%.
o 8e@iion re$ei@e" M+2 27, 200%.
o A$$epte" -ul2 1>, 200%.
1!i 4or0 4+ upporte" b2 t!e 8epubli$ o? *lo@eni+ Minitr2 o? He+lt!;
Minitr2 o? :"u$+tion, *$ien$e +n" *port Gr+nt 0%817518, 3%7%>%5 (M./. +n"
M.P.), P0750%7010%, +n" *lo7.* 2001&%> (A.P.); +n" t!e :urope+n .nion7?un"e"
proMe$t oHum+n 1r+nmiible *pon'i?orm :n$ep!+lop+t!ie: 1!e
5europ+t!olo'2 5et4or0 (P8)E5:1)p (M.P.). ;e +$0no4le"'e t!e +it+n$e o?
#r. Herbert /u"0+ ()ntitute o? 5eurolo'2, .ni@erit2 o? =ienn+, +n" Autri+n
8e?eren$e (entre ?or Hum+n Prion #ie+e, =ienn+, Autri+) +n" #r. -+me
)roni"e (5europ+t!olo'2 3+bor+tor2, (-# *ur@eill+n$e .nit, .ni@erit2 o?
:"inbur'!, :"inbur'!, .6), 4!o 0in"l2 pro@i"e" t!e +mple o? G** +n" @(-#
$erebell+r tiue.
(orrepon"en$e !oul" be +""ree" to #r. M+r+ /reM+n+$, )ntitute o?
P+t!op!2iolo'2, A+lo0+ >, *)71000 3MublM+n+, *lo@eni+. :7m+il:
m+M+.breM+n+$qm?.uni7lM.i.
(op2ri'!t r 200% *o$iet2 ?or 5euro$ien$e 027076>7>&0%&2%8029705s15.00&0
Pre@iou *e$tion

eferences
1.
A10&pp' ED2 K&p& :2 L"* ;2 4!or&%6Torr&% S2 S'$/'(*r$3/ N2 P&$r"# A2 Co!& GM2
S('!! G<2 H*'n1 SC2 B'rr"o ;R =2771> B"n0"n1 #3'r'#$&r"%$"#% o
r'0"o!*or"n'$&0 ?60"'!)/!'("no626n'p3$3/!&$3/!"0&n& 0&r".'$".&% '% po%"$ron
&("%%"on $o(o1r'p3/ "('1"n1 pro-&% or @6'(/!o"0 p!'A*&% "n A!B3&"(&rC%
0"%&'%&+ ; N&*ro%#" 21D RC189=169>+
Abtr+$t&P8:: Pull 1eLt
2.
B'#%)'" ;B2 K!*n) E<2 M'$3"% AC2 H/('n TB =2772> I('1"n1 '(/!o"06@ 0&po%"$%
"n .".o+ ; C&r&- B!oo0 4!oE M&$'- 22D 173961781+
Me"line
3.
B'rr"o ;R2 H*'n1 SC2 Co!& GM2 S'$/'(*r$3/ N2 P&$r"# A2 P3&!p% ME2 S('!! G<
=1999> PET I('1"n1 o $'n1!&% 'n0 p!'A*&% "n A!B3&"(&rC% 0"%&'%&+ ; N*#! M&0
87D F7P6F1P+
4.
D&Ar(on0 S;2 Kr&$B%#3('r HA2 Pr*%"n&r SB =2772> Pr"on 0"%&'%&%+ InD
Gr&&n"&!0C% n&*rop'$3o!o1/2 E0 F2 :o! 2 =Gr'3'( DI2 L'n$o% PE2 &0%>2 pp 2F36
323+ Lon0onD Arno!0+
5.
H'"n&!!n&r ;A2 Br'n$n&r6In$3'!&r S2 C&r.&nG)o.G L2 BroEn P2 K"$'(o$o T2
T'$&"%3" ;2 D"r"n1&r H2 L"-&r%)" PP2 R&1&!& H2 4&*#3$ M2 M'/r N2 <&%%&!/ P2
S*((&r K2 S&"$&!-&r1&r 42 B*0)' H =1999> T3& or"1"n'! G&r%$('nn6S$rH*%%!&r6
S#3&"n)&r '("!/ o A*%$r"'D 0".&r1&n$ #!"n"#op'$3o!o1"#'! p3&no$/p&% -*$
#on%$'n$ PrP 1&no$/p&+ Br'"n P'$3o! 9D 2716211+
Me"line
6.
H&1/" I2 H'"n&!!n&r ;A2 4!"#)&r H2 Iron%"0& ;<2 H'*E ;;2 T'$&"%3" ;2 H'!$"' M2
B*1"'n" O2 A1*BB" A2 B*0)' H =199F> Pr"on pro$&"n "((*no#/$o#3&("%$r/D
r&!"'-!& %$'"n"n1 pro$o#o!2 "((*no(orp3o!o1/2 'n0 0"'1no%$"# p"$'!!%+ C!"n
N&*rop'$3o! 1?D 2?262?3+
7.
Iron%"0& ;<2 M#C'r0!& L2 Hor%-*r13 A2 L"( Z2 H&'0 M< =2772> P'$3o!o1"#'!
0"'1no%"% o .'r"'n$ Cr&*$B&!0$6;')o- 0"%&'%&+ APMIS 117D F968F+
(ro8e? Me"line
8.
;'#o-%on A2 P&$r"# A2 Ho1&n)'(p D2 S"n*r A2 B'rr"o ;R =199?> 1216D"#/'no626
=?60"(&$3/!'("non'p3$3'!&n626/!>prop&n& =DDNP>D ' %o!.&n$ po!'r"$/6'n0
."%#o%"$/6%&n%"$".& !*orop3or& or !*or&%#&n#& ("#ro%#op/+ ; A( C3&( So# 118D
99F2699F9+
(ro8e?
9.
K*n1 MP2 Ho* C2 Z3*'n1 ZP2 Z3'n1 B2 S)o.ron%)/ D2 Tro5'noE%)" ;Q2 L&& :M2
K*n1 H4 =2772> IMPID 'n "(pro.&0 $3"o!'."n6T 0&r".'$".& or "n .".o !'-&!"n1 o
@6'(/!o"0 p!'A*&%+ Br'"n R&% 99?D 2726217+
(ro8e? Me"line
10.
L'%(&B'% CI2 4o*rn"&r ;G2 No*.&! :2 Bo& H2 M'r#& D2 L'(o*r/ 42 Kopp N2
H'*E ;;2 Iron%"0& ;2 Br*#& M2 Dor(on$ D2 D&%!/% ;P =2771> A0'p$'$"on o $3&
-o."n& %pon1"or( &n#&p3'!op'$3/ '1&n$ $o pr"('$&% 'n0 #o(p'r"%on E"$3
Cr&*$B&!0$6;')o- 0"%&'%&D "(p!"#'$"on% or 3*('n 3&'!$3+ Pro# N'$! A#'0 S#"
USA 98D 81826818F+
11.
P&$r"# A2 ;'#o-%on A42 B'rr"o ;R =1998> 4*n#$"on'!"B'$"on o ' ."%#o%"$/6%&n%"$".&
!*orop3or& or pro-"n1 o -"o!o1"#'! %/%$&(%+ B"oor1 M&0 C3&( L&$$ 8D 18996
18?7+
(ro8e? Me"line
12.
Pr*%"n&r SB =1998> Pr"on%+ Pro# N'$! A#'0 S#" USA 99D 133?3613383+
13.
S#3n&!! SA2 S$'"n&% <A2 <&%%&n0or M< =1999> R&0*#$"on o !"po*%#"n6!")&
'*$o!*or&%#&n#& "n !*or&%#&n$!/ !'-&!&0 $"%%*&+ ; H"%$o#3&( C/$o#3&( 8FD F196
F37+
14.
S#o$$ MR2 <"!! R2 Iron%"0& ;2 N1*/&n HO2 Tr&(-!'/ P2 D&Ar(on0 S;2 Pr*%"n&r SB
=1999> Co(p&!!"n1 $r'n%1&n&$"# &."0&n#& or $r'n%("%%"on o -o."n& %pon1"or(
&n#&p3'!op'$3/ pr"on% $o 3*('n%+ Pro# N'$! A#'0 S#" USA 9?D 1913F619182+
15.
S3o13"6;'0"0 K2 S('!! G<2 A10&pp' ED2 K&p& :2 Er#o!" LM2 S"00'r$3 P2 R&'0 S2
S'$/'(*r$3/ N2 P&$r"# A2 H*'n1 SC2 B'rr"o ;R =2772> Lo#'!"B'$"on o
n&*ro"-r"!!'r/ $'n1!&% 'n0 @6'(/!o"0 p!'A*&% "n $3& -r'"n% o !"."n1 p'$"&n$% E"$3
A!B3&"(&r 0"%&'%&+ A( ; G&r"'$r P%/#3"'$r/ 17D 28639+
(ro8e? Me"line
16.
<"!! RG2 Iron%"0& ;<2 Z&"0!&r M2 Co*%&n% SN2 E%$"-&"ro K2 A!p&ro."$#3 A2 Po%&r
S2 Po##3"'r" M2 Ho('n A2 S("$3 PG =199?> A n&E .'r"'n$ o Cr&*$B&!0$6;')o-
0"%&'%& "n $3& UK+ L'n#&$ 38FD 9216929+
(ro8e? Me"line
17.
Z&"0!&r M2 S$&E'r$ GE2 B'rr'#!o*13 CR2 B'$&('n DE2 B'$&% D2 B*rn D;2
Co!#3&%$&r AC2 D*rE'r0 <2 4!&$#3&r NA2 H'E)"n% SA2 M'#)&nB"& ;M2 <"!! RG
=199F> N&E .'r"'n$ Cr&*$B&!0$6;')o- 0"%&'%&D n&*ro!o1"#'! &'$*r&% 'n0
0"'1no%$"# $&%$%+ L'n#&$ 397D 973697F+
(ro8e? Me"line
Jurnal G
Am - P+t!ol. 1999 5o@ember; 155(5): 1>5%1>57.
PM()#: PM(186696>
&electi7e Neuronal ,ulnerability in
+uman Prion "iseases
P+t+l P+mili+l )nomni+ #i??er ?rom Et!er 12pe o? Prion #ie+e
M+rin Guent$!e@, -uli+ ;+n$!it<, 1ill =oi'tl`n"er, Hel'+ Pli$0er, +n" Herbert /u"0+
Go to:
Abstract
Hum+n tr+nmiible pon'i?orm en$ep!+lop+t!ie (1*:) or prion "ie+e +re
neuro"e'ener+ti@e "ior"er o? in?e$tiou, in!erite" or por+"i$ ori'in +n" in$lu"e
(reut<?el"t7-+0ob "ie+e ((-#), Gertm+nn7*trùler7*$!ein0er "ie+e (G**), 0uru
+n" ?+t+l ?+mili+l inomni+ (PP)). (lini$op+t!olo'i$ ?e+ture o? PP) "i??er m+r0e"l2 ?rom
ot!er !um+n 1*:. Pre@iou tu"ie "emontr+te" ele$ti@e neuron+l @ulner+bilit2 o?
p+r@+lbumin poiti@e (P=[) GA/Aer'i$ in!ibitor2 interneuron in por+"i$ (-# +n"
eLperiment+l 1*:. )n t!i report 4e !o4 uni?orm e@ere lo o? P=[ neuron +lo in
ot!er 1*: u$! + G**, 0uru, ne4 @+ri+nt +n" ?+mili+l (-#. )n $ontr+t, t!ee neuron
+re motl2 4ell preer@e", or onl2 mo"er+tel2 re"u$e", in PP). Enl2 P=[ neuron
urroun"e" b2 iole$tin7/> poiti@e perineuron+l net 4ere e@erel2 +??e$te" in 1*:,
u''etin' + ?+$tor rei"in' in t!i t2pe o? eLtr+$ellul+r m+triL +roun" P=[ neuron +
mo"ul+tor ?or t!e ele$ti@e neuron+l @ulner+bilit2.
1r+nmiible pon'i?orm en$ep!+lop+t!ie (1*:) or prion "ie+e +re
neuro"e'ener+ti@e "ior"er o? in?e$tiou, in!erite", or por+"i$ ori'in (?or re@ie4 ee
8e?. 17%
). Hum+n 1*: in$lu"e (reut<?el"t7-+0ob "ie+e ((-#), Gertm+nn7*trùler7
*$!ein0er "ie+e (G**), 0uru, +n" ?+t+l ?+mili+l inomni+ (PP)). (-# i tr+"ition+ll2
$+te'ori<e" into t!e mot $ommon por+"i$ + 4ell + i+tro'eni$, ?+mili+l (?(-#) +n"
ne4 @+ri+nt (n@(-#) "ie+e, 4!i$! emer'e" in t!e p+t 2e+r in t!e .nite" 6in'"om.
>

*pon'i?orm $!+n'e, +tro'lioi, +n" neuron+l lo +re t!e $l+i$+l neurop+t!olo'i$+l
tri+" o? tiue leion in 1*:. ;!ere+ (-#, G**, +n" 0uru "ipl+2 o@erl+ppin' $lini$+l
+n" neurop+t!olo'i$+l ?e+ture, t!e $lini$+l preent+tion +n" neurop+t!olo'i$+l !+llm+r0
o? PP) i'ni?i$+ntl2 "i??er ?rom +ll ot!er !um+n 1*:.
5

8e$ent tu"ie !+@e ober@e" ele$ti@e @ulner+bilit2 o? "itin$t neuron+l ubet in
por+"i$ (-#, eLperiment+l (-#, +n" eLperiment+l $r+pie. 1!ee report !o4e" e+rl2,
e@ere +n" ele$ti@e lo o? p+r@+lbumin poiti@e (P=[) neuron,
6,7
4!i$! +re + ubet o?
GA/Aer'i$ interneuron; $orrel+tion bet4een tiue p+t!olo'2 +n" "itribution o? P=[
neuron,
8
+berr+nt neuropepti"e Y m85A in"u$tion, +n" "e$re+e o? neuropepti"e Y Y2
re$eptor bin"in' ite in t!e !ippo$+mpu o? $r+pie7in?e$te" mi$e.
9
1!ee ubet
pe$i?i$ $!+n'e 4ere u''ete" + poible b+i ?or ome o? t!e $lini$+l 2mptom in
1*:. Ho4e@er, ubet7pe$i?i$ p+t!olo'2 !+ not been in@eti'+te" in !um+n 1*: +p+rt
?rom por+"i$ (-#, u$! + G**, 0uru, PP), ?(-#, +n" n@(-#. )n t!i tu"2, 4e
in@eti'+te P=[ neuron in t!ee le $ommon t2pe o? !um+n 1*:.
Go to:
;e ue" ?ormol7?iLe", p+r+??in7embe""e" !um+n br+in tiue obt+ine" +t +utop2. Pi@e
PP) (t!ree m+le +n" t4o ?em+le p+tient, +'e r+n'e 2656 2e+r, prion protein (PrP) 'ene
(PRNP) 'enot2pe #1785; ?our !omo<2'ou +t t!e pol2morp!i$ PRNP $o"on 129 ?or
met!ionine (M), one un0no4n, in$lu"in' ?our $+e ?rom + ne4 Autri+n ?+mil2 reporte"
pre@ioul2
10,11
), ?our G** (t4o m+le +n" t4o ?em+le p+tient, +'e r+n'e %762 2e+r,
4it! PRNP 'enot2pe P1023 (>&>) +n" M129M (%&>, one un0no4n); in$lu"in' t4o $+e
?rom t!e ori'in+l Autri+n ?+mil2 reporte" pre@ioul2
12
), ?our ?(-# 4it! t!e PRNP
mut+tion :2006 (t4o m+le +n" t4o ?em+le p+tient, +'e r+n'e 5066 2e+r, in$lu"in'
one $+e 4it! $o"on =129= reporte" pre@ioul2
1%
), 1 0uru (1672e+r7ol" m+le, =129=;
5)H $+e 0in"l2 pro@i"e" b2 #r. P. 3iber0i, 3o"<, Pol+n", reporte" pre@ioul2
1>
), +n"
t4o n@(-# $+e (5172e+r7ol" m+le +n" 2772e+r7ol" ?em+le, M129M; 0in"l2 pro@i"e" b2
#r. -. )roni"e, :"inbur'!, .6; reporte" pre@ioul2
>
). 1!e ?ollo4in' re'ion 4ere
in@eti'+te": ?ront+l $orteL, $erebellum, !ippo$+mpu, +n" +"M+$ent tempor+l $orteL.
Hippo$+mp+l blo$0 ?rom t4o n@(-#, t4o ?(-#, +n" one PP) $+e 4ere not +@+il+ble
?or in@eti'+tion. A $ontrol, ei'!t ?ormol7?iLe" !um+n +utop2 br+in (?our m+le +n"
?our ?em+le p+tient, +'e r+n'e 2766 2e+r) 4it! norm+l !itolo'2 4ere ue".
;e per?orme" immuno!ito$!emitr2 ?or p+r@+lbumin (P=) +n" le$tin t+inin' 4it!
iole$tin7/> ()3/>) to "e$or+te perineuron+l net (P55) o? eLtr+$ellul+r m+triL +roun"
P=[ neuron.
15
14o mono$lon+l +ntibo"ie +'+int P= (P=72%5, PA8=719, bot! "ilute"
1:5000, *i'm+ (!emi$+l (o., *t. 3oui, ME) 4ere ue". *e$tion ?or P= l+belin' 4ere
boile" 10 minute in t+r'et retrie@+l olution (pH 9.9) (#+0o, Glotrup, #enm+r0). 3e$tin
t+inin' ()3/>7peroLi"+e l+bele", 10 b'&ml 1ri7bu??ere" +line, 1 !our; *i'm+) 4+
per?orme" on e$tion boile" ?or 10 minute in $itr+te7bu??ere" +line (pH 6.0). /ot! +nti7
P= +ntibo"ie !o4e" + imil+r "itribution o? P=7li0e immunore+$ti@it2, but t!e P=72%5
immunot+ine" e$tion !+" + better i'n+l7 to7b+$0'roun" r+tio +n" t!u 4ere m+inl2
ue" ?or e@+lu+tion.
Ou+nti?i$+tion 4+ m+"e blin"l2 b2 t4o o? u (M. G. +n" -. ;.). (ountin' b2 bot!
!o4e" @er2 imil+r reult; me+n @+lue 4ere entere" into ?in+l t+titi$+l e@+lu+tion.
P=[ neuron 4ere +ee" in t!e +me re'ion (?ront+l +n" tempor+l $orteL) o? $ontrol,
PP), G**, ?(-#, +n" n@(-# $+e b2 $ountin' immunopoiti@e $ell bo"ie in %
repreent+ti@e ?iel" 4it! + G20 obMe$ti@e. 1!e me+n o? +ll % ?iel" 4+ entere" into
t+titi$+l e@+lu+tion. 1!e tot+l number o? neuron 4ere e@+lu+te" in Ht:7t+ine"
e$tion o? $ontrol, PP), G**, ?(-#, +n" n@(-# $+e b2 $ountin' uneDui@o$+l neuron+l
$ell bo"ie in t!e % ?iel" eL+mine" 4it! + G>0 obMe$ti@e. 1!e me+n o? +ll % ?iel" 4+
entere" into t+titi$+l e@+lu+tion. 5euron+l $ell bo"ie 4ere 4ell "itin'ui!+ble ?rom
t!e !omo'eneoul2 re" $2topl+m o? re+$ti@e +tro$2te, 4!i$! +re +bun"+nt in 1*:.
1!e me+n re'ion+l number o? +ll +n" o? P=[ neuron 4ere $+l$ul+te" +n" tete" ?or
i'ni?i$+nt "i??eren$e in +ll 'roup ($ontrol, PP), +n" ot!er 1*:) uin' + 6ru0+l7;+lli
one74+2 ?ollo4e" b2 + t4o7t+ile" M+nn7;!itne2 U7tet.
Go to:
esults
$ontrols
(ontrol !+" + imil+r pro?ile o? re'ion7pe$i?i$ "itribution o? P=[ neuron, 4it! !i'!et
number in pre7 +n" p+r+ubi$ulum, ?ront+l (Pi'ure 1A) +n" tempor+l $orteL, mo"er+te
number in entor!in+l $orteL +n" ubi$ulum, +n" lo4 number in !ippo$+mp+l e$tor
(A1>. )n t!e $erebellum, Pur0inMe $ell 4ere tron'l2 poiti@e ?or p+r@+lbumin (Pi'ure
2() . 5euron 4it! )3/>[ P55 4ere "itribute" in t!e $orteL +n" !ippo$+mp+l
?orm+tion; in $ontr+t, )3/>[ P55 4ere not "ete$t+ble +roun" Pur0inMe $ell (Pi'ure
2A) . 1!e number o? )3/>[ P55 4+ !i'!er in t!e ?ront+l $orteL t!+n in t!e tempor+l
$orteL.
Pi'ure 1.
P+r@+lbumin immunot+inin' (A.$: G.I) +n" iole$tin7/> t+inin' ?or perineuron+l net
o? eLtr+$ellul+r m+triL (".3: /.*) in ?ront+l $orteL in $ontrol (A: "), PP) ((: %), G**
($: 3), n@(-# (G: /), ?(-# (+: '), +n" 0uru ( )))
Pi'ure 2.
)3/> t+inin' (A) o? + $ontrol $erebellum +n" p+r@+lbumin immunot+inin' o? + 0uru (()
+n" $ontrol ($) $erebellum. 1!ere i l+$0 o? )3/>[ P55 +roun" P=[ Pur0inMe $ell in
norm+l br+in; Pur0inMe $ell +re preer@e" in 0uru. Eri'in+l m+'ni?i$+tion: )))
Gerstmann-&tr>ussler-&cheinker "isease: /uru: 3amilial: and New
,ariant $reut-feldt-Jakob "isease
All $+e !o4e" 1*:7pe$i?i$ p+t!olo'2: pon'i?orm $!+n'e, +tro'lioi, neuron+l lo
(in t!e ?ront+l $orteL 22U S 2.% *:M + $omp+re" to $ontrol) +n" PrP "epoition.
1!ee "i??erent 1*: t2pe !o4e" + uni?orm ubtot+l to tot+l lo o? P=[ neuron +n"
e@ere lo o? P= neuropil t+inin' in t!e ?ront+l ( 71U S 5.0 *:M, P u 0.001; Pi'ure
1(, G, H, ) ; Pi'ure % ), tempor+l ( 57.>U S 16.7 *:M, P u 0.02) +n" entor!in+l
$orteL, pre7 +n" p+r+ubi$ulum +n" +ll re'ion o? t!e !ippo$+mpu, irrepe$ti@e o? t!e
lo$+l e@erit2 o? pon'i?orm $!+n'e or +tro'lioi. Enl2 one G** $+e !o4e" + norm+l
number o? P=[ neuron in t!e tempor+l $orteL. 1!e lo o? P=[ neuropil +n" 2n+pti$
button +ppe+re" more e@ere t!+n t!e lo o? P=[ $ell bo"ie (Pi'ure 1(, G, H, )) . 1!e
number +n" morp!olo'2 o? $erebell+r P=[ neuron (Pur0inMe $ell) +n" neuropil
+ppe+re" 4ell preer@e" (Pi'ure 2/) . 5euron 4it! )3/>[ P55 4ere e@erel2
"eplete" in +ll in@eti'+te" re'ion (Pi'ure 1P, 6, 3, M) , $on?irmin' t!e lo o? P=[
$ell. 1!e lo o? )3/>[ P55 eeme" to be more e@ere t!+n t!e lo o? P=[ neuron
(Pi'ure 1P, 6, 3, M) .
Pi'ure %.
Gr+p!i$ repreent+tion o? t!e number o? P=[ neuron in t!e ?ront+l $orteL. 1!e $olumn
"epi$t t!e +@er+'e number o? P=[ neuron in t!e ?ront+l $orteL (P u 0.001, 6ru0+l7
;+lli tet; BP K 0.02, $omp+re" to $ontrol; )))
3atal 3amilial Insomnia
All $+e !o4e" li'!t but @+ri+ble 1*:7pe$i?i$ p+t!olo'2: pon'i?orm $!+n'e
(retri$te" to t!+l+mu +n" one $orti$+l ?o$u e+$! in t!ree o? ?our br+in), +tro'lioi,
neuron+l lo (in t!e ?ront+l $orteL 1>U S 1.0 *:M + $omp+re" to $ontrol), +n" in
t4o $+e ?o$+l PrP "epoition. All $+e !o4e" mo"er+te lo ( %8U S 8.1 *:M; P u
0.02) o? P=[ neuron in t!e ?ront+l $orteL (Pi'ure 1/ +n" %) 4!ere t!e neuropil
t+inin' +ppe+re" onl2 li'!tl2 re"u$e" (Pi'ure 1/) . 1!ere 4+ + t+titi$+ll2
i'ni?i$+nt "i??eren$e bet4een ?ront+l $orti$+l number o? P=[ neuron in PP) +n" +ll
ot!er 1*: (P u 0.005) (Pi'ure %) . )n tempor+l ( 16.6U S 7.25 *:M lo + $omp+re"
to $ontrol, P F 0.7) +n" entor!in+l $orteL, pre7 +n" p+r+ubi$ulum, +ll re'ion o? t!e
!ippo$+mpu +n" t!e $erebellum, P=[ neuron 4ere 4ell preer@e". Morp!olo'2 o? P=[
neuron in +ll in@eti'+te" re'ion 4+ norm+l (Pi'ure 1/) . )3/>[ P55 +ppe+re" to
be li'!tl2 re"u$e" in t!e ?ront+l $orteL (Pi'ure 1:) but 4ere "ene in +ll ot!er
in@eti'+te" re'ion, epe$i+ll2 in t!e tempor+l $orteL.
Go to:
"iscussion
5euron+l ubet "em+r$+te" b2 $+l$ium bin"in' protein (e', p+r@+lbumin, $+lbin"in,
$+lretinin) !+@e been re$entl2 "emontr+te" to be ele$ti@el2 @ulner+ble or reit+nt in
neuro"e'ener+ti@e "ior"er u$! + Al<!eimerX "ie+e,
16,17
P+r0inonX "ie+e,
18

Pi$0X "ie+e,
19
+n" ot!er. Pre@iou report b2 our +n" ot!er 'roup !+@e !o4n +
e@ere +n" ele$ti@e lo o? P=[ neuron in por+"i$ (-#,
678
4!i$! "e@elope" +lre+"2
@er2 e+rl2 in eLperiment+l 1*:.
7
1!i 4+ u''ete" + + poible ubtr+te o? t2pi$+l
2mptom in t!ee "ior"er u$! + m2o$lonu +n" $!+r+$teriti$ ::G p+ttern.
678
1!e
ubet7pe$i?i$ neuron+l @ulner+bilit2 4+ re$entl2 $orrobor+te" b2 e@ere lo o? P55
in por+"i$ (-#
20
+n" eLperiment+l 1*:.
7
Here 4e "e$ribe lo o? t!e P=[ ubet o?
GA/Aer'i$ neuron in ot!er t2pe o? 1*:. 1!e "e$re+e o? + e$on" m+r0er ?or t!e P=[
ubet o? GA/Aer'i$ neuron, )3/>, $on?irm t!e lo o? t!i neuron+l ubet. P= i
lo$+li<e" in mot $orti$+l GA/Aer'i$ neuron
21
(20 to 25U o? +ll neuron in t!e ?ront+l
$orteL +re GA/Aer'i$
22
), +n" t!e tot+l neuron+l lo @+rie ?rom 1> to 22U in our
$ount. 1!i reult u''et t!+t t!e P=[ ubet ?orm t!e m+in 'roup o? neuron lot in
1*:. 1!e "iproportion+te lo o? P=[ neuron to t!e tot+l neuron+l lo reporte" !ere
+n" in pre@iou report
7,8
u''et t!+t "+m+'e o? t!i p+rti$ul+r ubet i not
$oneDuen$e o? t!e lo$+l e@erit2 o? t!e p+t!olo'i$+l pro$e, but more li0el2 + prim+r2
e@ent.
(lini$+ll2 +n" neurop+t!olo'i$+ll2, PP) $le+rl2 "i??er ?rom +ll ot!er !um+n 1*:. 1iue
p+t!olo'2 in PP) ?o$ue on t!e t!+l+mu, +n" t!ere i little or no "ete$t+ble tiue
p+t!olo'2 in t!e $orteL.
11
*urpriin'l2, PP) !o4 onl2 mo"er+te (+ $omp+re" to +ll
ot!er !um+n 1*: in our erie) lo o? P=[ neuron +n" neuropil t+inin' in t!e ?ront+l
$orteL, +ppe+rin' to be t!e onl2 uneDui@o$+l "i??ue p+t!olo'i$+l $!+n'e in t!e PP)
$orteL. 1!i mo"er+te lo o? $orti$+l P=[ neuron li0el2 +$$ount ?or t!e li'!t tot+l
neuron+l $orti$+l lo in PP). Ho4e@er, t!i neuron+l ubet i 4ell preer@e" in t!e
tempor+l $orteL +n" +"M+$ent !ippo$+mpu, in tri0in' $ontr+t to +ll ot!er 1*: t2pe.
1!i +"" +not!er element to t!e eL$eption+l poition o? PP) +mon' !um+n 1*:. )t i
poible t!+t ome "i??eren$e in $lini$+l preent+tion o? PP), + $omp+re" 4it! ot!er
1*:, mi'!t be "ue to t!e better preer@+tion o? P=[ $orti$+l neuron.
(orti$+l but not $erebell+r P=[ neuron (Pur0inMe $ell)
7
+re ele$ti@el2 @ulner+ble in
1*:. 14o +ttribute "i$rimin+te Pur0inMe $ell ?rom +ll ot!er P=[ neuron: $o7
eLpreion o? +not!er $+l$ium bin"in' protein, $+lbin"in,
7
+n" l+$0 o? )3/>[ P55. 1!e
?+$t t!+t P=[ neuron "e@oi" ?rom )3/>[ P55 u$! + Pur0inMe $ell +re uu+ll2 4ell
preer@e" in 1*: +n" t!+t lo o? )3/>[ P55 +ppe+re" to be e@en more e@ere t!+n
lo o? P=[ neuron
7,20
u''et + ?+$tor rei"in' in t!e eLtr+$ellul+r m+triL +roun"
$orti$+l or !ippo$+mp+l P=[ neuron + mo"ul+tor ?or t!eir @ulner+bilit2. )t rem+in to be
et+bli!e" !o4 $+l$ium bin"in' protein +n" t!e eLtr+$ellul+r m+triL inter+$t to $on?er
u$! ele$ti@e neuron+l @ulner+bilit2 or reit+n$e in 1*:, repe$ti@el2.
Go to:
Acknowledgments
;e t!+n0 epe$i+ll2 #r. -+me )roni"e, :"inbur'!, .6 ?or +llo4in' u to ue li"e
?rom t4o n@(-# br+in. M. (. 6+rner i 0in"l2 +$0no4le"'e" ?or eL$ellent te$!ni$+l
+it+n$e, #r. Peter /irner ?or !elpin' 4it! t+titi$, +n" #r. -o!+nne H+in?ellner ?or
!elp +n" upport.
Go to:
3ootnotes
A""re reprint reDuet to #r. H. /u"0+, )ntitute o? 5eurolo'2, .ni@erit2 o? =ienn+,
A6H 0>-, ;`!rin'er G9rtel 1820, PE/ >8, A71097 ;ien, Autri+. :7m+il:
!.bu"0+q+0!74ien.+$.+t.
*upporte" b2 :urope+n .nion /iome"72 (on$erte" A$tion oHum+n 1r+nmiible
*pon'i?orm :n$ep!+lop+t!ie (Prion #ie+e): 5europ+t!olo'2 +n" P!enot2pi$
=+ri+tionp (ProMe$t 3e+"er: H. /u"0+) +n" :urope+n .nion /iome"72 *!+re" (ot
A$tion oMole$ul+r /iolo'2 o? Prion #ie+ep (ProMe$t 3e+"er: -. (ollin'e, 3on"on).
M. Guent$!e@ +n" -. ;+n$!it< $ontribute" eDu+ll2 to t!i 4or0.
Go to:
eferences
1. Hor4i$! A3, ;eim+n -*: #e+"l2 $on?orm+tionprotein mi?ol"in' in prion "ie+e.
(ell 1997, 89:>997510. IPubMe"J
2. Pruiner */, *$ott M8, #eArmon" *-, (o!en P:: Prion protein biolo'2. (ell 1998,
9%:%%77%>8. IPubMe"J
%. Pruiner */: 1!e prion "ie+e. /r+in P+t!ol 1998, 8:>99751%. IPubMe"J
>. ;ill 8, )roni"e -, Aei"ler M, (ouen *, :tibeiro 6, Alpero@it$! A, Poer *,
Po$$!i+ri M, Ho?m+n A, *mit! P: A ne4 @+ri+nt o? (reut<?el"t7-+0ob "ie+e in t!e .6.
3+n$et 1996, %>7:9217926. IPubMe"J
5. P+r$!i P, Peteren 8/, (!en *G, Autilio7G+mbetti 3, (+pell+ri *, Mon+ri 3, (ortelli P,
Mont+'n+ P, 3u'+rei :, G+mbetti P: Mole$ul+r p+t!olo'2 o? ?+t+l ?+mili+l inomni+.
/r+in P+t!ol 1998, 8:5%975>8. IPubMe"J
6. Perrer ), (++ 8, 8i@er+ 8: P+r@+lbumin7immunore+$ti@e $orti$+l neuron in
(reut<?el"t7-+0ob "ie+e. Ann 5eurol 199%, %>:86>7866. IPubMe"J
7. Guent$!e@ M, Gro$!up MH, 6or"e0 8, 3iber0i PP, /u"0+ H: *e@ere, e+rl2, +n"
ele$ti@e lo o? + ubpopul+tion o? GA/Aer'i$ in!ibitor2 neuron in eLperiment+l
tr+nmiible pon'i?orm en$ep!+lop+t!ie. /r+in P+t!ol 1998, 8:615762%. IPubMe"J
8. Guent$!e@ M, H+in?ellner -A, 1r+b+ttoni G8, /u"0+ H: #itribution o? p+r@+lbumin7
immunore+$ti@e neuron in br+in $orrel+te 4it! !ippo$+mp+l +n" tempor+l $orti$+l
p+t!olo'2 in (reut<?el"t7-+0ob "ie+e. - 5europ+t!ol :Lp 5eurol 1997, 56:11197112>.
IPubMe"J
9. #ie< M, 6oitin+!o -, #eArmon" *-, Grot! #, Pruiner */, Ho0?elt 1: M+r0e"
"e$re+e o? neuropepti"e Y Y2 re$eptor bin"in' ite in t!e !ippo$+mpu in murine prion
"ie+e. Pro$ 5+tl A$+" *$i .*A 1997, 9>:1%26771%272. IPM( ?ree +rti$leJ IPubMe"J
10. /u"0+ H, Almer G, H+in?ellner -A, /r9$0e 1, -ellin'er 6: 1!e Autri+n PP) $+e.
/r+in P+t!ol 1998, 8:55>. IPubMe"J
11. Almer G, H+in?ellner -A, /r9$0e 1, -ellin'er 6, 6leinert 8, /+2er G, ;in"l E,
6ret<$!m+r HA, Hill A, *i"le 6, (ollin'e -, /u"0+ H: P+t+l ?+mili+l inomni+: + ne4
Autri+n ?+mil2. /r+in 1999, 122:5716. IPubMe"J
12. H+in?ellner -A, /r+ntner7)nt!+ler *, (er@en+0o@+ 3, /ro4n P, 6it+moto 1, 1+tei!i -,
#irin'er H, 3iber0i PP, 8e'ele H, Peu$!t M, /u"0+ H: 1!e ori'in+l Gertm+nn7
*trùler7*$!ein0er ?+mil2 o? Autri+: "i@er'ent $lini$op+t!olo'i$+l p!enot2pe but
$ont+nt PrP 'enot2pe. /r+in P+t!ol 1995, 5:2017211. IPubMe"J
1%. H+in?ellner -, P+r$!i P, 6it+moto 1, -+riu (, G+mbetti P, /u"0+ H: A no@el
p!enot2pe in ?+mili+l (reut<?el"t7-+0ob "ie+e: prion protein 'ene :2006 mut+tion
$ouple" 4it! @+line +t $o"on 129 +n" t2pe 2 prote+e reit+nt prion protein. Ann 5eurol
1999, >5:8127816. IPubMe"J
1>. H+in?ellner -A, 3iber0i PP, Guiro2 #(, (er@en+0o@+ 3, /ro4n P, G+M"ue0 #(,
/u"0+ H: P+t!olo'2 +n" immuno$2to$!emitr2 o? + 0uru br+in. /r+in P+t!ol 1997,
7:5>7755%. IPubMe"J
15. (elio M8: Perineuron+l net o? eLtr+$ellul+r m+triL +roun" p+r@+lbumin7$ont+inin'
neuron o? t!e !ippo$+mpu. Hippo$+mpu 199%, %:55760. IPubMe"J
16. /r+"2 #8, Mu?on :-: P+r@+lbumin7immunore+$ti@e neuron in t!e !ippo$+mp+l
?orm+tion o? Al<!eimerX "ie+e" br+in. 5euro$ien$e 1997, 80:111%71125. IPubMe"J
17. *olo"0in A, =el"!ui<en *, =+n7Hoeen G: (ontin'ent @ulner+bilit2 o? entor!in+l
p+r@+lbumin7$ont+inin' neuron in Al<!eimerX "ie+e. - 5euro$i 1996, 16:%%117%%21.
IPubMe"J
18. )to H, Goto *, *+0+moto *, Hir+no A: (+lbin"in7#280 in t!e b++l '+n'li+ o? p+tient
4it! P+r0inonim. Ann 5eurol 1992, %2:5>%7550. IPubMe"J
19. Ar+i H, 5o'u$!i ), M+0ino Y, 6o+0+ 6, Hei<m+nn (;, )i<u0+ 8: P+r@+lbumin7
immunore+$ti@e neuron in t!e $orteL in Pi$0X "ie+e. - 5eurol 1991, 2%8:2007202.
IPubMe"J
20. /eli$!en0o P, Mi0lo2 -, /eler /, /u"0+ H, (elio M: :+rl2 "etru$tion o? t!e
eLtr+$ellul+r m+triL +roun" p+r@+lbumin7immunore+$ti@e interneurone in por+"i$ $+e
o? (reut<?el"t7-+0ob #ie+e. 5eurobiol #i 1999, 6:2697279. IPubMe"J
21. (elio M8: P+r@+lbumin in mot R7+minobut2ri$ +$i"7$ont+inin' neuron o? t!e r+t
$erebr+l $orteL. *$ien$e 1986, 2%1:9957997. IPubMe"J
22. Hornun' -, 1ribolet 5: (!emi$+l or'+ni<+tion o? t!e !um+n $erebr+l $orteL. 1r+$e2 #
e". 5eurotr+nmitter in t!e Hum+n /r+in. 1995, :pp >1760 Plenum Pre, 5e4 Yor0 +n"
3on"on.
Jurnal B
962
=):;*
%
*A=:*
5
*HA8:*
Epen A$$e Peer78e@ie4e"
8ee+r$! Arti$le
&od1 "eficiency educes Incubation Time
in *ouse *odels of Prion "isease
*!+!een A0!t+r,
-uli+ Gri<en0o@+,
A"+m ;enborn,
Hol'er Hummeri$!,
M+r Pern+n"e< "e M+r$o,
*eb+ti+n /r+n"ner,
-o!n (ollin'e,
*+r+! :. 3lo2" m+il
Arti$le
About t!e Aut!or
Metri$
(omment
8el+te" (ontent
12
Hi"e Pi'ure
Abtr+$t
)ntro"u$tion
M+teri+l +n" Met!o"
8eult
#i$uion
*upportin' )n?orm+tion
A$0no4le"'ment
Aut!or (ontribution
8e?eren$e
8e+"er (omment (0)
Pi'ure
Abstract
Prion in?e$tion, $+uin' neuro"e'ener+ti@e $on"ition u$! + (reut<?el"t7-+0ob "ie+e
+n" 0uru in !um+n, $r+pie in !eep +n" /*: in $+ttle +re $!+r+$terie" b2 prolon'e"
+n" @+ri+ble in$ub+tion perio" t!+t +re ?+it!?ull2 repro"u$e" in moue mo"el.
)n$ub+tion time i p+rtl2 "etermine" b2 'eneti$ ?+$tor in$lu"in' pol2morp!im in t!e
prion protein 'ene. Ou+ntit+ti@e tr+it lo$i tu"ie in mi$e +n" !um+n 'enome74i"e
+o$i+tion tu"ie !+@e $on?irme" t!+t multiple 'ene +re in@ol@e". (+n"i"+te 'ene
+ppro+$!e !+@e +lo been ue" +n" i"enti?ie" App, I!16r1 +n" So01 + +??e$tin'
in$ub+tion time. )n t!i tu"2 4e loo0e" ?or +n +o$i+tion bet4een App, I!16r1 +n"
So01 repreent+ti@e *5P +n" prion "ie+e in$ub+tion time in t!e 5ort!port
!etero'eneou to$0 o? mi$e ino$ul+te" 4it! t!e (!+n"ler&8M3 prion tr+in. 5o
+o$i+tion 4+ een 4it! App, !o4e@er, i'ni?i$+nt +o$i+tion 4ere een 4it! I!16r1 (P
F 0.02) +n" So01 (PK0.0001) u''etin' t!+t pol2morp!im +t t!ee lo$i $ontribute to
t!e n+tur+l @+ri+tion ober@e" in in$ub+tion time. Purt!ermore, ?ollo4in' $!+llen'e 4it!
(!+n"ler&8M3, M:7 +n" M8(2 prion tr+in, *o"1 "e?i$ient mi$e !o4e" !i'!l2
i'ni?i$+nt re"u$tion in in$ub+tion time o? 20, 1% +n" 2>U, repe$ti@el2. 5o "i??eren$e
4ere "ete$te" in *o"1 eLpreion or +$ti@it2. Eur "+t+ $on?irm t!e prote$ti@e role o?
en"o'enou *o"1 in prion "ie+e.
$itation4 A0!t+r *, Gri<en0o@+ -, ;enborn A, Hummeri$! H, Pern+n"e< "e M+r$o M, et
+l. (201%) *o"1 #e?i$ien$2 8e"u$e )n$ub+tion 1ime in Moue Mo"el o? Prion #ie+e.
P3o* E5: 8(1): e5>>5>. "oi:10.1%71&Mourn+l.pone.005>>5>
%ditor4 -i2+n M+, E!io *t+te .ni@erit2, .nite" *t+te o? Ameri$+
ecei7ed4 5o@ember 19, 2012; Accepted4 #e$ember 11, 2012; Published4 -+nu+r2 22,
201%
$opyright4 r 201% A0!t+r et +l. 1!i i +n open7+$$e +rti$le "itribute" un"er t!e
term o? t!e (re+ti@e (ommon Attribution 3i$ene, 4!i$! permit unretri$te" ue,
"itribution, +n" repro"u$tion in +n2 me"ium, pro@i"e" t!e ori'in+l +ut!or +n" our$e +re
$re"ite".
3unding4 1!i 4or0 4+ ?un"e" b2 t!e .6 Me"i$+l 8ee+r$! (oun$il (444.mr$.+$.u0).
1!e ?un"er !+" no role in tu"2 "ei'n, "+t+ $olle$tion +n" +n+l2i, "e$iion to publi!,
or prep+r+tion o? t!e m+nu$ript.
$ompeting interests4 -( i + "ire$tor +n" !+re!ol"er o? #7Gen limite", +n +$+"emi$
pin7out $omp+n2 in t!e ?iel" o? prion "i+'noi, "e$ont+min+tion +n" t!er+peuti$. 1!i
"oe not +lter t!e +ut!orX +"!eren$e to +ll t!e P3E* Ene poli$ie on !+rin' "+t+ +n"
m+teri+l.
Introduction
Prion "ie+e or tr+nmiible pon'i?orm en$ep!+lop+t!ie (1*:) +re pro'rei@e
neuro"e'ener+ti@e "ie+e 4!i$! +re in@+ri+bl2 ?+t+l. 1!e2 in$lu"e (reut<?el"t7-+0ob
"ie+e ((-#) in !um+n, bo@ine pon'i?orm en$ep!+lop+t!2 in $+ttle (/*:) +n" $r+pie
in !eep +n" 'o+t I1J. 1!e2 +re tr+nmiible mi?ol"e" protein "ie+e $+ue" b2 t!e
$on@erion o? norm+l $ellul+r prion protein (PrP
(
) to +bnorm+l io?orm, 0no4n + PrP
*$
.
)n +""ition to PrP
*$
+$$umul+tion t!e2 +re $!+r+$terie" b2 pon'i?orm @+$uol+tion,
'lioi +n" neuron+l lo in t!e br+in.
Prion "ie+e in$ub+tion time in eLperiment+l moue mo"el i rem+r0+bl2 $onitent i?
eLperiment+l p+r+meter +re 0ept $ont+nt, !o4e@er, t!ere i $oni"er+ble @+ri+tion
bet4een "i??erent inbre" tr+in o? mi$e u''etin' + tron' 'eneti$ $ontribution. 1!e
prion protein 'ene, Prnp, i t!e m+Mor $omponent 4!ere !omo<2'ou 0no$0out mi$e +re
$ompletel2 reit+nt to prion prop+'+tion +n" "ie+e, !emi<2'ou 0no$0out mi$e !+@e +
prolon'e" in$ub+tion time +n" PrP o@ereLpreor !+@e + mu$! !orter in$ub+tion time
t!+n 4il" t2pe mi$e I2J, I%J. )n$ub+tion time i +lo mo"ul+te" b2 + n+tur+ll2 o$$urrin'
pol2morp!im in Prnp 4!ere Prnp
'
(10873eu, 18971!r) +n" Prnp
-
(1087P!e, 1897=+l)
+re +o$i+te" !ort +n" lon' in$ub+tion time repe$ti@el2 I>JI8J. *imil+rl2, +
met!ionine to @+line pol2morp!im +t $o"on 129 o? !um+n PrP i +lo + m+Mor
u$eptibilit2 ?+$tor ?or !um+n prion "ie+e I9JI1%J. Mot inbre" line o? mi$e +re
Prnp
'
+n" 4it!in t!ee t!ere i till $oni"er+ble @+ri+tion in in$ub+tion time t!u
impli$+tin' ot!er 'ene I1>J. Ou+ntit+ti@e tr+it lo$i tu"2 in mi$e I15JI19J +n" 'enome7
4i"e +o$i+tion tu"ie (G;A*) in !um+n I1%J, I20J u''et t!+t +lt!ou'! Prnp i t!e
in'le mot import+nt ?+$tor, t!e $ombine" e??e$t o? e@er+l ot!er 'ene +re +lo o?
import+n$e.
)n +""ition to tr+"ition+l m+ppin' te$!niDue, in"i@i"u+l $+n"i"+te 'ene +ppro+$!e !+@e
+lo been emplo2e" to i"enti?2 'ene t!+t in?luen$e prion "ie+e in$ub+tion time.
14ent2 $+n"i"+te 'ene 4ere $reene" b+e" on p+t!4+2 +n" 'ene pre@ioul2
impli$+te" in prion "ie+e b2 tetin' 0no$0out or tr+n'eni$ moue mo"el I21J. .n"er
t!ee $on"ition, mot 'ene !+" no e??e$t on in$ub+tion time, !o4e@er, 0no$0out o? App
(+m2loi" pre$uror protein), I!16r1 (interleu0in 1 re$eptor 1) +n" o@ereLpreion o?
!um+n SOD1 (uperoLi"e "imut+e 1) in$re+e" ur@i@+l b2 1%, 16 +n" 19U
repe$ti@el2.
1o tet 4!et!er App, I!16r1 +n" So01 $ontribute to t!e n+tur+ll2 o$$urrin' @+ri+tion in
inbre" line o? mi$e 4e ue" + !etero'enou to$0 (H*) o? mi$e ino$ul+te" 4it! t!e
(!+n"ler&8o$02 Mount+in 3+bor+tor2 (8M3) moue7+"+pte" $r+pie prion tr+in to loo0
?or + t+titi$+l +o$i+tion bet4een prion "ie+e in$ub+tion time +n" t!ee 'eneti$ lo$i
I22JI25J. 1!e So01 lo$u pro"u$e" + !i'!l2 i'ni?i$+nt +o$i+tion t!ere?ore 4e
in@eti'+te" t!i ?urt!er b2 $!+llen'in' So01 "e?i$ient mi$e (So01
JKJ
) 4it! t!ree "i??erent
prion tr+in.
%thics &tatement
All pro$e"ure 4ere $on"u$te" in +$$or"+n$e 4it! intitution+l, .6 +n" intern+tion+l
re'ul+tion +n" t+n"+r" on +nim+l 4el?+re +n" $on?orm to A88)=: 'ui"eline I26J.
:t!i$+l +ppro@+l 4+ 'r+nte" b2 t!e Me"i$+l 8ee+r$! (oun$il (M8() Prion .nit et!i$
$ommittee +n" $+rrie" out un"er .6 Home E??i$e li$en$e PP370&727>.
*ice
5ort!port H* mi$e (Gi?t ?rom 8. Hit<em+nn, Portl+n", Ere'on, .*A) 4ere bre" +n"
prion in$ub+tion time 4ere $olle$te" ?or mi$e +t 'ener+tion %7 (n F 1052) + pre@ioul2
"e$ribe" I22J. So01 0no$0out mi$e (/6;129*77*o"1
tm13eb
&-) 4ere obt+ine" ?rom t!e
-+$0on 3+bor+tor2 (/+r H+rbor, M+ine, .*A) +n" b+$0$roe" to (57/3&6- to Q57
(Gi?t ?rom :M( Pi!er, .ni@erit2 (olle'e 3on"on )ntitute o? 5eurolo'2, 3on"on, .6)
I27J. 1!e reultin' !etero<2'ote +nim+l (So01
JKL
) 4ere inter$roe" to pro@i"e
!omo<2'ote 0no$0out (So01
JKJ
) +n" 4il" t2pe litter m+te $ontrol (So01
LKL
). Et!er
inbre" moue line 4ere pro@i"e" b2 H+rl+n, .6 3t". (/i$eter, .6).
Prion Inoculation and Phenotyping
)no$ul+ 4ere m+"e ?rom t!e br+in o? termin+ll2 i$0 mi$e + 1U (4ei'!t&@olume)
!omo'en+te in #7P/*. 1!e (!+n"ler&8M3 ()9900), M:7 ()9>59) +n" M8(2 ()9>68)
prion tr+in 4ere our$e" +n" prep+re" + pre@ioul2 "e$ribe" I22J, I28J. Mi$e 4ere
+n+et!eti<e" 4it! io?luor+ne&E2 +n" ino$ul+te" intr+7$erebr+ll2 into t!e ri'!t p+riet+l
lobe 4it! %0 Vl o? ino$ul+ + pre@ioul2 "e$ribe" I15J. 1o minimie +nim+l u??erin',
mi$e 4ere eL+mine" "+il2 ?or $lini$+l i'n o? prion "ie+e +n" 4ere $ulle" on$e +
"e?initi@e "i+'noi !+" been m+"e or e+rlier i? !o4in' +n2 i'n o? "itre or ot!er
!e+lt! problem. Mi$e 4ere 0ille" b2 eLpoure to $+rbon "ioLi"e '+ in riin'
$on$entr+tion. (riteri+ ?or "e?inin' $r+pie in mi$e 4ere + pre@ioul2 "e$ribe" I29J.
)n$ub+tion time 4+ "e?ine" + t!e number o? "+2 ?rom ino$ul+tion to "i+'noi. All
pro$e"ure 4ere $on"u$te" in +$$or"+n$e 4it! intitution+l, .6 +n" intern+tion+l
re'ul+tion +n" t+n"+r" on +nim+l 4el?+re +n" $on?orm to A88)=: 'ui"eline I26J.
:t!i$+l +ppro@+l 4+ 'r+nte" b2 t!e M8( Prion .nit et!i$ $ommittee +n" $+rrie" out
un"er .6 Home E??i$e li$en$e PP370&727>.
P$ and &e9uencing
#5A ?or e+$! o? t!e !etero'eneou to$0 p+rent+l line 4+ obt+ine" ?rom t!e -+$0on
3+bor+tor2 (/+r H+rbor, M+ine, .*A). P(8 +n" eDuen$in' re+$tion 4ere $+rrie" out +
pre@ioul2 "e$ribe" I2%J +n" run on + %7%0 $+pill+r2 eDuen$er (Applie" /io2tem).
Genotyping
#5A 4+ eLtr+$te" ?rom t!e H* $ro mi$e + pre@ioul2 "e$ribe" I2%J. *5P
'enot2pin' 4+ $+rrie" out uin' t!e Alleli$ #i$rimin+tion ?un$tion on + 7500 P+t
8e+l7time P(8 m+$!ine (Applie" /io2tem) uin' 8oLMe'+MiL Gol" (Mi$ro<one,
3t") + pre@ioul2 "e$ribe" I2%J. Primer +n" probe +re !o4n in 1+ble *1.
eal-time T-P$
;!ole br+in 85A 4+ eLtr+$te" ?rom unin?e$te" (68 4ee0 ol") mi$e +n" re@ere
tr+n$ribe" uin' AM= re@ere tr+n$ript+e +n" r+n"om primer + pre@ioul2 "e$ribe"
I29J. (ontrol re+$tion 4ere $+rrie" out 4it! no re@ere7tr+n$ription ?or e+$! +mple to
enure no 'enomi$ #5A $ont+min+tion o? t!e 85A prep+r+tion. 8e+l7time 817P(8
re+$tion 4ere $+rrie" out on + 7500 P+t 8e+l7time P(8 *2tem (Applie" /io2tem)
+ pre@ioul2 "e$ribe" I29J. So01 1+Dm+n Gene :Lpreion ++2 (3i?e 1e$!nolo'ie)
4+ "upleLe" 4it! e+$! o? t!ree en"o'enou $ontrol (GAPDH, @6'#$"n +n" T3/61> I2%J.
All re+$tion 4ere $+rrie" out in tripli$+te. All "+t+ p+e" + norm+lit2 tet +n" 4+
t+titi$+ll2 e@+lu+te" uin' + t7tet.
5estern (lotting
Por "ete$tion o? PrP
*$
b2 4etern blottin' 10U (4ei'!t&@olume) br+in !omo'en+te in #7
P/* 4ere prep+re" b2 ribol2in'. *+mple 4ere ben<on+e tre+te" +n" protein+e 6
"i'ete" (50 V'&ml o? protein+e 6 ?or 1 ! +t %7n() +n" blotte" + "e$ribe" pre@ioul2
I%0J. PrP 4+ "ete$te" 4it! +nti7PrP mono$lon+l +ntibo"2 )(*M%5 (#7Gen 3t", .6)
I%1J +n" +l0+line7p!op!+t+e7$onMu'+te" +nti7moue )'G e$on"+r2 +ntibo"2 (*i'm+7
Al"ri$!) "e@elope" in t!e $!emilumine$ent ubtr+te (#P7*t+r (1ropiL )n$). Por
"ete$tion o? *o"1, +mple 4ere prep+re" + +bo@e but 4it!out protein+e 6 "i'etion
+n" "ete$te" 4it! + r+bbit pol2$lon+l +ntibo"2 (0.5 u'&ml) (Ab$+m). Anti7m7+$tin moue
mono$lon+l +ntibo"2 (0.05 u'&ml) (*i'm+) 4+ ue" + +n intern+l $ontrol + pre@ioul2
"e$ribe" I28J.
Immunohistochemistry
Moue br+in 4ere ?iLe" in 10U bu??ere" ?orm+l +line (/P*) +n" prion in?e$te" tiue
4+ tre+te" in 98U ?ormi$ +$i" ?or one !our to remo@e in?e$ti@it2. 1iue 4ere p+r+??in
4+L embe""e", e$tione" +n" t+ine" + pre@ioul2 "e$ribe" I29J. *e$tion 4ere t+ine"
4it! !+em+toL2lin +n" eoin (Ht:) ?or 'ener+l @ie4in' in$lu"in' +ement o?
pon'ioi +n" neuron+l lo. #ie+e +o$i+te" prion "epoition 4+ @iu+lie" 4it!
+nti7PrP mono$lon+l +ntibo"2 )(*M%5 (#7Gen 3t", .6) +n" 'lioi 4+ "etermine"
4it! +n +nti7'li+l ?ibrill+r2 +$i" protein (GPAP) +ntibo"2 (#+0o 3t", .6).
1uantification of PrP
c
10U (4ei'!t&@olume) br+in !omo'en+te 4ere ue" to me+ure en"o'enou le@el o?
PrP
$
b2 en<2me lin0e" immunoorbent ++2 (:3)*A) + pre@ioul2 "e$ribe" I%2J. 1ot+l
protein $on$entr+tion 4+ me+ure" uin' + Pier$e /(A protein ++2 0it (1!ermo
*$ienti?i$) +$$or"in' to t!e m+nu?+$turerX intru$tion.
&upero8ide "ismutase %n-ymatic Acti7ity Assay
1ot+l *E# +$ti@it2 4+ me+ure" in 10U 4ei'!t&@olume (20 mM H:P:*, pH 7.2, 1 mM
:G1A, 210 mM m+nnitol, 70 mM u$roe) br+in !omo'en+te uin' + *E# ++2 0it
((+lbio$!em) +$$or"in' to t!e M+nu?+$turerX intru$tion. A (oom+ie (/r+"?or")
protein ++2 0it (/io78+") 4+ ue" to me+ure t!e tot+l protein $on$entr+tion +$$or"in'
to t!e m+nu?+$turerX intru$tion.
&tatistical Analysis
*t+titi$+l tet 4ere $+rrie" out uin' Gr+p!P+" )n*t+t (Gr+p!P+" *o?t4+re, )n$,
(+li?orni+, .*A) +n" *P** ()/M). 1!e 6+pl+n7Meier lo'7r+n0 tet 4+ ue" to +n+l2e
ur@i@+l "+t+.
esults
Association &tudies
1o loo0 ?or +n +o$i+tion bet4een App, I!16r1, So01 +n" prion "ie+e in$ub+tion time
4e ue" t!e 5ort!port H* o? mi$e + pre@ioul2 "e$ribe" I22J, I2%J, I25J, I%%J. 1!e
to$0 4+ 'ener+te" ?rom ei'!t p+rent+l line (A&-, A68&-, /A3/&$-, (%H&He-,
(57/3&6-, (/A&-, #/A&2- +n" 3P&-) +n" n F 1052 mi$e ?rom 'ener+tion %7 4ere
ino$ul+te" 4it! t!e (!+n"ler&8M3 moue +"+pte" $r+pie prion tr+in I22J.
)nbre" line o? mi$e +re $loel2 rel+te", !o4e@er, it i eLpe$te" t!+t multiple in'le
nu$leoti"e pol2morp!im (*5P) 4ill be preent bet4een t!e p+rent+l line o? t!e H*
mi$e. 1o ele$t t!e mot +"@+nt+'eou *5P ?or 'enot2pin' 4e eDuen$e" t!e $o"in'
re'ion, untr+nl+te" re'ion (.18), put+ti@e promoter (+ pre"i$te" b2 P8E*(A5
(4447bim+.$it.ni!.'o@&molbio&pro$+n) +n" ?l+n0in' introni$ eDuen$e. Prom t!i "+t+
4e "e?ine" t!e m+Mor tr+in "itribution p+ttern (*#P) +$ro t!e p+rent+l line. 1!i 4+
ubeDuentl2 $on?irme" b2 $omp+rion 4it! 'enomi$ eDuen$in' "+t+ *5P 'ener+te" b2
t!e *+n'er )ntitute (444.+n'er.+$.u0&$'i7bin&mo"elor'&moue 'enome&np.pl) 4!i$!
$o@ere" t!e entire 'ene t+rtin' ?rom 5 0b uptre+m o? t!e 5_.18. 1!e m+in *#P ?or
e+$! lo$u +n" t!e tot+l number o? *5P i !o4n in t+ble 1. 1o $+pture e+$! *#P, one
t+''in' *5P 4+ $!oen ?or 'enot2pin' (1+ble 2). Por one *#P o? App +n" I!16r12 *5P
4ere $!oen b+e" on put+ti@e ?un$tion+l i'ni?i$+n$e (G(P bin"in' ite +n" +mino +$i"
$!+n'e repe$ti@el2). Et!er *5P 4ere $!oen b+e" on t!eir +bilit2 to t+' t!e *#P.
Genot2pin' 4+ $+rrie" out in +pproLim+tel2 >00 mi$e repreentin' t!e eLtreme o? t!e
in$ub+tion time "itribution + t!i $+pture mot o? t!e po4er o? t!e $ro I25J. Por
"et+il o? primer +n" probe ee 1+ble *1. Por App, t4o *5P 4ere tete", repreentin'
t4o *#P (1+ble 1 +n" 2). r>7601%25 i lo$+te" in t!e promoter 4it!in + G(P bin"in'
ite (P8E*(A5) +n" r>69%>600 i 4it!in intron 2 +n" i not 0no4n to be + ?un$tion+l
@+ri+nt. 5eit!er o? t!ee *5P !o4e" +n +o$i+tion 4it! in$ub+tion time (1+ble 2). Ene
non72non2mou I!16r1 $o"in' pol2morp!im (Al+71=+l) ?rom eLon % (1+ble 2) 4+
tete" +n" t!i !o4e" + i'ni?i$+nt +o$i+tion 4it! in$ub+tion perio" (P F 0.02,
6ru0+l7;+lli non7p+r+metri$ A5E=A) 4!ere t!e (( 'enot2pe 4+ +o$i+te" 4it! +
!ort in$ub+tion time (1>>S1.6, me+n ("+2) S em) +n" t!e 11 'enot2pe 4it! + lon'er
in$ub+tion time (155S%.%). 1!e !etero<2'ou +llele (1 4+ not i'ni?i$+ntl2 "i??erent
?rom (( (1>5S1.7) u''etin' + "omin+nt mo"e o? +$tion. An +lleli$ tet (M+nn7
;!itne2) +lo !o4e" + i'ni?i$+nt +o$i+tion (P F 0.007, ( +llele 1>>S1.0 +n" 1 +llele
1>9S1.>) (1+ble 2). A So01 *5P ?rom intron % (1+ble 2), o? no 0no4n ?un$tion, +lo
!o4e" + !i'!l2 i'ni?i$+nt +o$i+tion 4it! prion "ie+e in$ub+tion time (PK0.0001,
6ru0+l7;+lli non7p+r+metri$ A5E=A) 4!ere t!e GG 'enot2pe 4+ +o$i+te" 4it! +
!ort in$ub+tion time (1%2[>.7) +n" t!e AA 'enot2pe 4it! + lon'er in$ub+tion time
(1>9[1.5). )n $ontr+t to I!16r1, t!e So01 +llele +ppe+r to be!+@e in +n +""iti@e 4+2 4it!
t!e !etero<2'ou +llele GA !+@in' +n interme"i+te me+n in$ub+tion time (1>1S1.8). 1!e
+lleli$ tet (M+nn7;!itne2) +lo !o4e" + !i'!l2 i'ni?i$+nt +o$i+tion (PK0.0001, G
+llele 1>0S1.7 +n" A +llele 1>7S1.0) (1+ble 2).
#o4nlo+":
PP1
Po4erPoint li"e
P5G
l+r'er im+'e (>86/)
1)PP
ori'in+l im+'e (1116/)
Table 1) *aHor strain distribution patterns genotyped for +& mice)
"oi:10.1%71&Mourn+l.pone.005>>5>.t001
#o4nlo+":
PP1
Po4erPoint li"e
P5G
l+r'er im+'e (556/)
1)PP
ori'in+l im+'e (1996/)
Table 6) &NP genotyping in +& mice)
"oi:10.1%71&Mourn+l.pone.005>>5>.t002
Sod1 mNA %8pression
/+e" on t!e +o$i+tion tu"2 "+t+ I!16r1 +n" So01 lo$i +re +o$i+te" 4it! prion "ie+e
in$ub+tion time, !o4e@er, So01 !+ t!e tron'et e??e$t 4it! + me+n "i??eren$e o? 17 "+2
bet4een t!e !omo<2'ou 'enot2pe $omp+re" to 11 "+2 ?or t!e I!16r1 'enot2pe,
t!ere?ore, 4e onl2 ?ollo4e" up t!e So01 "+t+. 5o 0no4n ?un$tion+l pol2morp!im 4ere
?oun" in t!e H* p+rent+l tr+in ?or So01 +n" o 4e me+ure" So01 m85A eLpreion
le@el in unin?e$te" br+in ?rom t!e p+rent+l line o? t!e H* (eL$ept 3P) to ee 4!et!er
en"o'enou eLpreion le@el 4+ +o$i+te" 4it! 'enot2pe. So01 m85A eLpreion
le@el 4ere Du+nti?ie" uin' re+l time 817P(8. Alt!ou'! @+ri+tion bet4een t!e inbre"
line 4+ een (Pi'ure 1A), 4!en 'roupe" b2 So01 'enot2pe (A F A, /A3/, (%H, (57;
G F A68, (/A, #/A) t!i 4+ not i'ni?i$+nt (Pi'ure 1/). ;e +lo +4 no "i??eren$e in
*o"1 protein eLpreion b2 4etern blot bet4een A +n" G +llele mi$e eit!er in unin?e$te"
or (!+n"ler&8M3 in?e$te" mi$e (Pi'ure 1(#).
#o4nlo+":
PP1
Po4erPoint li"e
P5G
l+r'er im+'e (7926/)
1)PP
ori'in+l im+'e (2.69M/)
3igure 1) Sod1 e8pression in mouse brain)
P+nel A +n" /. Ou+nti?i$+tion o? So01 m85A eLpreion in 4!ole br+in b2 re+l7time 817
P(8. 5 F 6 ?or +ll 'roup +n" +mple 4ere run in tripli$+te. All +mple 4ere "upleLe"
?or So01 (P+m7l+bel) +n" +n en"o'enou $ontrol GAPDH2 @6'#$"n or T3/61 (=i$7l+bel).
:Lpreion le@el i eLpree" in +rbitr+r2 unit + norm+lie" b2 t!e 'eometri$ me+n o?
t!e Du+ntit2 o? t!e en"o'enou $ontrol (/7+Li). :rror b+r repreent t!e t+n"+r"
"e@i+tion. (A) So01 m85A eLpreion le@el ?or p+rent+l tr+in o? t!e H* mi$e (eL$ept
3P). (/) So01 m85A eLpreion le@el 'roupe" b2 +llele (A&G) (A F A, /A3/, (%H,
(57; G F A68, (/A, #/A). 5o i'ni?i$+nt "i??eren$e 4+ ober@e" bet4een t!e 'roup.
P+nel (() +n" (#). Ou+nti?i$+tion o? *o"1 protein in 4!ole br+in (10U !omo'en+te,
4ei'!t&@olume) ?rom n F % A +llele mi$e ((57/l&6) +n" G +llele mi$e (P=/&5). P=/&5
mi$e 4ere ue" to repreent + G +llele tr+in r+t!er t!+n +n H* p+rent+l tr+in "ue to
+@+il+bilit2 o? tiue. *+mple 4ere immunoblotte" 4it! r+bbit pol2$lon+l +nti7!um+n
*E#1(Ab$+m) +n" "ete$te" 4it! )8#2e800(; ('reen) $onMu'+te" 'o+t +nti7r+bbit )'G
(3i7(or). Anti7m7+$tin moue mono$lon+l +ntibo"2 (*i'm+) 4+ +lo in$lu"e" + +
lo+"in' $ontrol +n" 4+ "ete$te" uin' )8#2e680 (re") $onMu'+te" 'o+t +nti7moue )'G
(3i7(or). Pluore$en$e 4+ @iu+lie" uin' +n E"2e2 in?r+7re" im+'er (3i7(or). (()
.nino$ul+te" mi$e, (#) 1ermin+ll2 i$0 (!+n"ler&8M3 prion ino$ul+te" mi$e.
"oi:10.1%71&Mourn+l.pone.005>>5>.'001
Transmission of Prions to Sod1
/
*ice
)t 4+ pre@ioul2 reporte" t!+t o@ereLpreion o? !um+n *E#1 in + tr+n'eni$ moue
mo"el in$re+e" prion "ie+e in$ub+tion time 4it! t!e 8M3 prion tr+in, !o4e@er, t!i
4+ not repli$+te" 4it! t!e %01 = (/*: p++'e" in Prnp
-
+llele mi$e, /6.)) tr+in I21J.
1!ee tr+nmiion 4ere $+rrie" out in m+ll 'roup (n F > or 5), on + miLe" 'eneti$
b+$0'roun" +n" in t!e preen$e o? + ?orei'n protein, t!ere?ore, to $l+ri?2 t!e role o? *o"1
4e tr+nmitte" t!ree "i??erent prion tr+in to *o"1 "e?i$ient mi$e. ;e ue" So01
0no$0out mi$e /6;129*77*o"1
tm13eb
&- b+$0$roe" to (57/3&6- (So01
JKJ
) +n" t!eir litter
m+te (So01
LKL
) + 4il" t2pe $ontrol I27J. Alt!ou'! mut+tion in !um+n *E#1 +re
+o$i+te" 4it! ?+mili+l +m2otrop!i$ l+ter+l $leroi (?A3*), So01 "e?i$ient mi$e +re
neurolo'i$+ll2 norm+l +n" "o not "e@elop pont+neou neuro"e'ener+ti@e "ie+e. 1!e
onl2 p!enot2pe +o$i+te" 4it! t!ee mi$e i ?em+le terilit2 in !omo<2'ote 0no$0out
I27J. ;e ino$ul+te" mi$e intr+$erebr+ll2 4it! t4o "i??erent moue7+"+pte" $r+pie prion
tr+in, (!+n"ler&8M3 +n" M:7, +n" + moue +"+pte" /*: prion tr+in, M8(2 (/*:
p++'e" in Prnp
'
mi$e) I28J, I%>J. )n So01
JKJ
mi$e + i'ni?i$+nt "e$re+e in in$ub+tion
time 4+ een ?or +ll t!ree prion tr+in + $omp+re" to So01
LKL
$ontrol (Pi'ure 2 +n"
1+ble *2). Por (!+n"ler&8M3 prion t!e me+n in$ub+tion time ("+2 S em) 4+ re"u$e"
b2 20U ?rom 156S1 in So01
LKL
to 125S1 in So01
JKJ
mi$e (PK0.0001, 6+pl+n7Meier lo'
r+n0 ur@i@+l) +n" ?or M:7 t!e me+n in$ub+tion time 4+ re"u$e" b2 1%U ?rom 16>S2 in
So01
LKL
to 1>2S5 in So01
JKJ
mi$e (PK0.0001, 6+pl+n7Meier lo' r+n0 ur@i@+l). Por M8(2
t!e me+n in$ub+tion time 4+ re"u$e" b2 2>U ?rom 178S2 in So01
LKL
to 1%6S7 in So01
JK
J
mi$e (PK0.0001, 6+pl+n7Meier lo' r+n0 ur@i@+l). 1!ee "+t+ 4ere obt+ine" uin'
?em+le mi$e, !o4e@er, imil+r reult 4ere +lo re$or"e" ?or m+le mi$e +lt!ou'! t!e
me+n "i??eren$e 4ere re"u$e" to 16, 5 +n" 1%U ?or (!+n"ler&8M3, M:7 +n" M8(2
prion tr+in repe$ti@el2 (1+ble *2).
#o4nlo+":
PP1
Po4erPoint li"e
P5G
l+r'er im+'e (1126/)
1)PP
3igure 6) /aplan-*eier sur7i7al cur7es)
#+t+ +re !o4n + U o? +nim+l (?em+le) ur@i@in' (27+Li) plotte" +'+int t!e number o?
"+2 pot ino$ul+tion (L7+Li). (A) 1r+nmiion o? (!+n"ler&8M3 prion tr+in to So01
JKJ
+n" So01
LKL
(;1) litter m+te $ontrol (/) 1r+nmiion o? M:7 prion tr+in to So01
JKJ

+n" So01
LKL
(;1). (() 1r+nmiion o? M8(2 moue +"+pte" /*: prion tr+in to So01
JK
J
+n" So01
LKL
(;1). A re"u$tion in me+n in$ub+tion time o? 20U, 1%U, +n" 2>U 4+
een in A7( repe$ti@el2. 1!i re"u$tion in ur@i@+l 4+ t+titi$+ll2 i'ni?i$+nt ?or e+$!
tr+nmiion (PK0.001, 6+pl+n7Meier lo'7r+n0 ur@i@+l tet).
"oi:10.1%71&Mourn+l.pone.005>>5>.'002
Prion tr+in $+n be "i??erenti+te" b2 bio$!emi$+l "i??eren$e in PrP
*$
or b2 p+ttern o?
neurop+t!olo'2 in re$ipient +nim+l. ;etern blottin' o? br+in ?rom in?e$te" +nim+l
$on?irme" t!+t t!ere i no $!+n'e to t!e PrP
*$
t2pe $+ue" b2 repli$+tion in t!e +ben$e o?
*o"1 (Pi'ure %). P+t!olo'i$+l e@+lu+tion 4+ $+rrie" out on br+in e$tion ?rom So01
JKJ

+n" So01
LKL
mi$e ?or e+$! tr+nmiion 4it! p+rti$ul+r +ttention to PrP
*$
"epoition,
pon'ioi, 'lioi +n" neuron+l lo (Pi'ure >, Pi'ure *1 +n" *2). Por (!+n"ler&8M3
tr+nmiion, t!e p+ttern o? 'lioi +n" PrP
*$
t+inin' i imil+r, !o4e@er, PrP
*$
t+inin' i
p+t$!ier ?or t!e So01
JKJ
p+rti$ul+rl2 in t!e $orteL. 5o !ippo$+mp+l neuron+l lo i een
in So01
JKJ
mi$e 4!ile mil" neuron+l lo i een in 4il" t2pe +nim+l. 5o "i??eren$e +re
een bet4een t!e t4o 'roup o? mi$e ?ollo4in' M:7 in?e$tion. Por M8(2 tr+nmiion
t!ere i no "i??eren$e in t!e p+ttern o? 'lioi +n" PrP
*$
"epoition, !o4e@er, t!ere i +
re"u$e" intenit2 o? t+inin' epe$i+ll2 in t!e $orteL tripe in t!e So01
JKJ
mi$e +
$omp+re" to 4il" t2pe. 5euron+l lo in t!e !ippo$+mpu i @er2 @+ri+ble ?or t!e M8(2
tr+nmiion, !o4e@er, t!ere i no $le+r "i??eren$e bet4een t!e t4o 'roup o? mi$e.
#o4nlo+":
PP1
Po4erPoint li"e
P5G
l+r'er im+'e (2.7%M/)
1)PP
ori'in+l im+'e (2.>M/)
3igure ;) 5estern blots of PrP
&c
from infected mouse brains)
10U 4&@ br+in !omo'en+te (n F % per 'roup) 4ere "i'ete" 4it! protein+e 6 +n"
immunoblotte" 4it! +nti7PrP mono$lon+l +ntibo"2 )(*M%5 (#7Gen 3t", .6). (A)
1r+nmiion o? (!+n"ler&8M3 prion to So01
JKJ
+n" So01
LKL
(;1) litter m+te $ontrol.
(/) 1r+nmiion o? M:7 prion tr+in to So01
JKJ
+n" So01
LKL
(;1) litter m+te $ontrol.
(() 1r+nmiion o? M8(2 moue +"+pte" /*: prion tr+in to So01
JKJ
+n" So01
LKL
(;1)
litter m+te $ontrol. 5o "i??eren$e 4ere een bet4een t!e t4o 'roup re'+r"le o? prion
tr+in.
"oi:10.1%71&Mourn+l.pone.005>>5>.'00%
#o4nlo+":
PP1
Po4erPoint li"e
P5G
l+r'er im+'e (10.11M/)
1)PP
ori'in+l im+'e (9.>%M/)
3igure @) *' histology)
Hitolo'i$+l ?e+ture o? (!+n"ler&8M3 prion tr+nmiion to So01
JKJ
(A() +n" 4il"
t2pe $ontrol (#P) mi$e. P+nel A +n" # !o4 "itribution o? "ie+e7+o$i+te" PrP b2
immuno!ito$!emitr2 uin' +nti7PrP mono$lon+l +ntibo"2 )(*M%5. P+nel /, (, : +n"
P !o4 "et+il ?rom t!e !ippo$+mpu +n" +re t+ine" 4it! !+em+toL2lin +n" eoin (Ht:)
to @iu+lie pon'i?orm $!+n'e +n" neuron+l lo. 1!ere i +lmot no neuron+l lo in t!e
So01
JKJ
mi$e but mil" neuron+l lo i een in t!e 4il" t2pe +nim+l. E@er+ll, t!e p+ttern
o? pon'ioi, 'lioi +n" PrP "itribution +re imil+r bet4een t!e t4o 'roup, !o4e@er,
t!e "itribution o? "ie+e7+o$i+te" PrP i p+t$!ier in t!e 0no$0out epe$i+ll2 in t!e
$orteL. *$+le b+r $orrepon" to % mm (A, #), 660 Vm (/, :) or 160 Vm ((, P).
"oi:10.1%71&Mourn+l.pone.005>>5>.'00>
;e !+@e !o4n t!+t @+ri+tion +t t!e So01 lo$u i +o$i+te" 4it! prion "ie+e
in$ub+tion time +n" t!+t t!i i not eLpl+ine" b2 "i??eren$e in m85A eLpreion le@el.
;e t!ere?ore loo0e" +t *o"1 protein le@el b2 4etern blot in So01
LKL
$ontrol mi$e
in?e$te" 4it! (!+n"ler&8M3, M:7 +n" M8(2 prion +n" $omp+re" t!ee 4it! +'e
m+t$!e" $ontrol (P/* ino$ul+te" mi$e). 5o "i??eren$e 4ere een bet4een t!e ?our
'roup (Pi'ure 5A). ;e +lo $on?irme" t!+t t!e So01
JKJ
mi$e ue" in t!ee eLperiment
"i" not eLpre +n2 "ete$t+ble *o"1 protein (Pi'ure 5/). Alt!ou'! t!e +mount o? *o"1
+ppe+r t!e +me in unin?e$te" +n" in?e$te" mi$e it i poible t!+t *o" en<2me +re
more +$ti@e in t!e en@ironment $re+te" b2 prion in?e$tion. ;e t!ere?ore me+ure" tot+l
*o" en<2m+ti$ +$ti@it2 in So01
LKL
mi$e in?e$te" 4it! e+$! o? t!ree prion tr+in +n"
$omp+re" t!ee to unin?e$te" +nim+l. 5o i'ni?i$+nt "i??eren$e 4ere een bet4een t!e
'roup (Pi'ure 5().
#o4nlo+":
PP1
Po4erPoint li"e
P5G
l+r'er im+'e (7>86/)
1)PP
3igure G) 1uantification of &od and PrP
$
. 10U 4ei'!t&@olume br+in !omo'en+te immunoblotte" 4it! r+bbit pol2$lon+l +nti7
!um+n *E#1 (Ab$+m) +n" "ete$te" 4it! )8#2e800(; ('reen) $onMu'+te" 'o+t +nti7
r+bbit )'G (3i7(or). Anti7m7+$tin moue mono$lon+l +ntibo"2 (*i'm+) 4+ +lo in$lu"e"
+ + lo+"in' $ontrol +n" 4+ "ete$te" uin' )8#2e680 (re") $onMu'+te" 'o+t +nti7moue
)'G (3i7(or). Pluore$en$e 4+ @iu+lie" uin' +n E"2e2 in?r+7re" im+'er (3i7(or).
(A) /r+in ?rom So01
LKL
4il" t2pe mi$e ino$ul+te" 4it! P/* $omp+re" 4it! en" t+'e
*o"1
[&[
4il" t2pe mi$e ino$ul+te" 4it! 8M3, M:7 +n" M8(2 prion tr+in. 5o
"i??eren$e 4ere een bet4een t!e 'roup. (/) .nin?e$te" mi$e. (() 1ot+l *E#
en<2m+ti$ +$ti@it2 in 10U (4&@) So01
LKL
(;1) br+in. /r+in ?rom termin+ll2 i$0 mi$e
in?e$te" 4it! 8M3, M:7 +n" M8(2 4ere $omp+re" 4it! unin?e$te" mi$e. *+mple 4ere
run in tripli$+te 4it! n F 6 ?or e+$! 'roup. #+t+ +re !o4n norm+lie" b2 tot+l protein
$ontent (V'&ml) + "etermine" b2 + /r+"?or" protein ++2 (me+n S t+n"+r" "e@i+tion).
5o i'ni?i$+nt "i??eren$e 4+ een bet4een t!e 'roup. (#) PrP
$
le@el in So01
JKJ
+n"
So01
LKL
(;1) litter m+te $ontrol mi$e b2 :3)*A. PrP
$
le@el (V'&ml) 4ere "etermine" in
tripli$+te uin' 10U (4ei'!t&@olume) br+in !omo'en+te ?or So01
JKJ
(n F %) +n" So01
LKL
(n
F %) in + PrP pe$i?i$ :3)*A I%2J. #+t+ +re !o4n norm+lie" b2 tot+l protein $ontent
(V'&ml +n" L 1000) + "etermine" b2 + /(A ++2 (me+n S t+n"+r" "e@i+tion). 5o
i'ni?i$+nt "i??eren$e 4+ een bet4een t!e t4o 'roup.
"oi:10.1%71&Mourn+l.pone.005>>5>.'005
)n eLperiment+l moue mo"el t!e le@el o? PrP
$
eLpreion !+ + pro?oun" e??e$t on
in$ub+tion time t!ere?ore it i poible t!+t t!e re"u$tion in in$ub+tion time ober@e" in
So01
JKJ
mi$e $oul" be t!e reult o? +n upre'ul+tion o? t!e en"o'enou le@el o? PrP
$
I2J,
I%J. ;e tete" t!i b2 me+urin' tot+l PrP
$
le@el in + PrP pe$i?i$ :3)*A in *o"1
H&H
+n"
So01
LKL
mi$e I%2J. 5o i'ni?i$+nt "i??eren$e 4+ ober@e" (Pi'ure 5#).
"iscussion
Ou+ntit+ti@e tr+it lo$i m+ppin' in mi$e +n" G;A* in !um+n !+@e $on?irme" t!+t
multiple 'ene in +""ition to Prnp in?luen$e prion "ie+e in$ub+tion time +n"
u$eptibilit2 I1%J, I15J, I17J, I18J, I20J. 1!ee tu"ie !+@e u$$e?ull2 i"enti?ie"
$+n"i"+te lo$i but no in"i@i"u+l 'ene !+@e 2et been $on?irme" + ?un$tion+ll2
i'ni?i$+nt. Altern+ti@e tr+te'ie !+@e in$lu"e" t+r'etin' 'ene ?rom p+t!4+2
impli$+te" in prion "ie+e +n" tetin' t!em "ire$tl2 in moue mo"el. 1!i i"enti?ie"
App, I!16r1 +n" So01 + interetin' $+n"i"+te, !o4e@er, it "i" not +""re 4!et!er or not
t!e2 $ontribute" to t!e n+tur+l @+ri+tion I21J. )n t!i tu"2 4e $+rrie" out +n +o$i+tion
tu"2 ?or e+$! o? t!ee 'ene in H* o? mi$e. 1!e m+ppin' reolution +@+il+ble in t!e H*
$ro +t 'ener+tion %7 i +pproLim+tel2 12 $M 4!i$! i too bi' to un+mbi'uoul2
+$ribe +n +o$i+tion to one 'ene +lt!ou'! m+ppin' to *#P m+2 !elp to n+rro4 "o4n
t!e re'ion I25J.
App i + @er2 promiin' $+n"i"+te 'ene p+rti$ul+rl2 'i@en it in@ol@ement in Al<!eimerX
"ie+e (A#), + neuro"e'ener+ti@e protein mi?ol"in' "ie+e. 1!ere i +lo in$re+in'
e@i"en$e ?or +n inter+$tion 4it! PrP 4!ere PrP !+ been impli$+te" in pot7tr+nl+tion+l
pro$ein' o? APP t!rou'! t!e in!ibition o? /A(:1 +n" in ome moue mo"el PrP m+2
bin" +m2loi"7m +n" me"i+te +pe$t o? it neurotoLi$it2 I%5JI%8J. #epite it +ttr+$tion
+ + $+n"i"+te 4e "i" not ?in" +n2 e@i"en$e o? +n +o$i+tion 4it! prion "ie+e
in$ub+tion time in t!i $ro +lt!ou'! it i poible t!+t ot!er *#P not tete" b2 u m+2
!o4 ome +o$i+tion. App m+2 till !+@e + role in prion "ie+e +lt!ou'! it "oe not
+ppe+r to $ontribute to t!e n+tur+l @+ri+tion ober@e" in t!e p+rent+l line o? t!i $ro.
)l17r1 i + re$eptor ?or t!e pro7in?l+mm+tor2 $2to0ine, )l71, pro"u$e" b2 'li+ +n"
impli$+te" in t!e "ie+e pro$e + + reult o? eLteni@e 'lioi. I!16r1 0no$0out mi$e
!+@e been pre@ioul2 tu"ie" $on?irmin' t!+t "eletion o? I!16r1 i prote$ti@e in mo"el o?
moue $r+pie I21J, I%9J. )n t!i tu"2 4e i"enti?2 + non72non2mou *5P (Al+71=+l) on
+ *#P t!+t i lin0e" to prion "ie+e in$ub+tion time. )t i not $le+r 4!et!er t!i *5P i
t!e ?un$tion+l @+ri+nt or 4!et!er it i $+rrie" 4it!in t!e +me !+plot2pe blo$0.
*o"1 i +n ubiDuitoul2 eLpree" $2topl+mi$ uperoLi"e "imut+e t!+t prote$t $ell
?rom oLi"+ti@e "+m+'e b2 remo@in' uperoLi"e t!rou'! $on@ertin' it to !2"ro'en
peroLi"e. )t !+ been +o$i+te" 4it! ot!er neuro"e'ener+ti@e "ie+e not+bl2
+m2otrop!i$ l+ter+l $leroi 4!ere mut+tion in !um+n *E#1 +$$ount ?or v20U o?
?+mili+l A3* $+e prob+bl2 @i+ + toLi$ '+in o? ?un$tion I>0J. *o"1 !+ +lo been
impli$+te" in Al<!eimerX "ie+e 4!ereb2 So01 0no$0out +$$eler+te" +m2loi"7m
oli'omeri+tion +n" memor2 lo in +n A# moue mo"el +n" $on@erel2 o@ereLpreion
o? *o"1 re$ue t!e $erebr+l en"ot!eli+l "2?un$tion in +not!er A# mo"el I>1J, I>2J. )n
t!i tu"2 4e !+@e !o4n + !i'!l2 i'ni?i$+nt +o$i+tion 4it! t!e So01 lo$u +n" prion
"ie+e in$ub+tion time t!ereb2 $on?irmin' it e??e$t on t!e n+tur+l @+ri+tion 4it!in t!ee
inbre" line o? mi$e. 1!e ?un$tion+l *5P rem+in un0no4n +n" 4e !+@e not "ete$te" +n2
e@i"en$e ?or "i??erenti+l m85A or protein eLpreion. ;e !+@e +lo $on?irme" t!e role o?
*o"1 + + prote$ti@e ?+$tor in prion "ie+e + "eletion o? *o"1 i'ni?i$+ntl2 re"u$e
in$ub+tion time in t4o "i??erent tr+in o? moue +"+pte" $r+pie ((!+n"ler&8M3 +n"
M:7) +n" + moue p++'e" /*: prion tr+in, M8(2. 1!ee "+t+ bro+"l2 +'ree 4it!
pre@ioul2 publi!e" "+t+ t!+t u''ete" + prote$ti@e e??e$t o? o@ereLprein' !um+n
*E#1 in mi$e $!+llen'e" 4it! 8M3 but not %01 = prion I21J. 1!i "i??eren$e m+2 be
eLpl+ine" b2 t!e preen$e o? t!e !um+n protein or b2 "i??eren$e in t!e moue +"+pte"
/*: tr+in $+ue" b2 p++'e in Prnp
-
r+t!er t!+n Prnp
'
mi$e. ;e $+nnot eL$lu"e t!e
poibilit2 t!+t t!e t+r'ete" 0no$0out o? *o"1 in t!ee mi$e m+2 in+"@ertentl2 +??e$t t!e
eLpreion o? +"M+$ent lo$i 4!i$! t!emel@e in?luen$e prion "ie+e in$ub+tion time +n"
t!+t t!i 4oul" eLpl+in t!e +ben$e o? "ete$t+ble "i??eren$e in *o"1 eLpreion.
ELi"+ti@e tre !+ been impli$+te" in neuro"e'ener+ti@e "ie+e +n" i $+ue" b2
eL$e re+$ti@e oL2'en pe$ie u$! + uperoLi"e +$$umul+tin' 4it! t!e $ell 4!i$! m+2
be t!e reult o? eL$e pro"u$tion b2 m+l?un$tionin' mito$!on"ri+ +n" "epletion o?
$+t+l2ti$ en<2me. )n moue mo"el o? prion "ie+e "+m+'e" mito$!on"ri+ !+@e been
"e$ribe" + 4ell + e@i"en$e ?or in$re+e" uperoLi"e 'ener+tion +n" ?ree r+"i$+l
"+m+'e I>%J, I>>J. M+r0er o? oLi"+ti@e "+m+'e !+@e +lo been "e$ribe" in (-# br+in
I>5J. ;e "i" not "ete$t + $!+n'e in *o"1 protein eLpreion or tot+l *o" +$ti@it2 in
repone to prion in?e$tion 4it! +n2 o? our prion tr+in, !o4e@er, t!e preen$e o? norm+l
*o"1 +$ti@it2 i $le+rl2 prote$ti@e + *o"1 "e?i$ient mi$e !o4 + i'ni?i$+ntl2 re"u$e"
in$ub+tion time +$ro +ll prion tr+in tete".
$onclusion
)n $on$luion, 4e !+@e !o4n t!+t bot! I!16r1 +n" So02 but not App2 +re +o$i+te" 4it!
t!e n+tur+l @+ri+tion in prion "ie+e in$ub+tion time me+ure" in t!e 5ort!port H* mi$e.
)n +""ition, *o"1 "e?i$ient mi$e !o4 !i'!l2 i'ni?i$+nt re"u$tion in in$ub+tion time o?
20, 1% +n" 2>U 4it! (!+n"ler&8M3, M:7 +n" M8(2 prion tr+in, repe$ti@el2.
Alt!ou'! no "i??eren$e in *o"1 eLpreion or +$ti@it2 4ere "ete$te" our "+t+ !i'!li'!t
t!e import+n$e o? oLi"+ti@e "+m+'e in prion "ie+e +n" t!e prote$ti@e role pl+2e" b2
en"o'enou *o"1 protein.
&upporting Information
Pi'ureT*1.ti?
1 & 2
?i' share
"o4nlo+"
*%I histology) Hitolo'i$+l ?e+ture o? M:7 prion tr+nmiion to So01
JKJ
(A() +n"
4il" t2pe $ontrol (#P) mi$e. P+nel A +n" # !o4 PrP
*$
"itribution b2 t+inin' 4it!
+nti7PrP mono$lon+l +ntibo"2 )(*M%5. P+nel /, (, : +n" P !o4 "et+il ?rom t!e
!ippo$+mpu +n" +re t+ine" 4it! !+em+toL2lin +n" eoin (Ht:) to @iu+lie
pon'i?orm $!+n'e +n" neuron+l lo. 5o "i??eren$e +re een bet4een t!e t4o 'roup.
*$+le b+r $orrepon" to % mm (A, #), 660 Vm (/, :) or 160 Vm ((, P).
3igure &1)
*%I histology) Hitolo'i$+l ?e+ture o? M:7 prion tr+nmiion to So01
JKJ
(A() +n"
4il" t2pe $ontrol (#P) mi$e. P+nel A +n" # !o4 PrP
*$
"itribution b2 t+inin' 4it!
+nti7PrP mono$lon+l +ntibo"2 )(*M%5. P+nel /, (, : +n" P !o4 "et+il ?rom t!e
pon'i?orm $!+n'e +n" neuron+l lo. 5o "i??eren$e +re een bet4een t!e t4o 'roup.
*$+le b+r $orrepon" to % mm (A, #), 660 Vm (/, :) or 160 Vm ((, P).
"oi:10.1%71&Mourn+l.pone.005>>5>.001
(1)P)
3igure &6)
*$6 histology) Hitolo'i$+l ?e+ture o? M8(2 prion tr+nmiion to So01
JKJ
(A()
+n" 4il" t2pe $ontrol (#P) mi$e. P+nel A +n" # !o4 PrP
*$
"itribution b2 t+inin'
4it! +nti7PrP mono$lon+l +ntibo"2 )(*M%5. P+nel /, (, : +n" P !o4 "et+il ?rom t!e
pon'i?orm $!+n'e +n" neuron+l lo. So01
JKJ
mi$e (#) !o4 + re"u$tion in PrP intenit2
rel+ti@e to 4il" t2pe mi$e epe$i+ll2 in t!e $orteL tripe. *$+le b+r $orrepon" to % mm
(A, #), 660 Vm (/, :) or 160 Vm ((, P).
"oi:10.1%71&Mourn+l.pone.005>>5>.002
(1)P)
Acknowledgments
;e +re 'r+te?ul to 8obert Hit<em+nn (#ep+rtment o? /e!+@iour+l 5euro$ien$e, Ere'on
He+lt! *$ien$e .ni@erit2, Portl+n", Ere'on, .*A) ?or t!e 0in" 'i?t o? t!e 5ort!port
Hetero'eneou *to$0 o? mi$e +n" Ann2 #e@o2 +n" :li<+bet! Pi!er ?or (57/36&-
b+$0$roe" So01 0no$0out mi$e. ;e +re 'r+te?ul to -+$0ie 3ine!+n +n" !er t+?? ?or
!itolo'2 +n" Hu"+ Al7#ouM+il2 +n" -on+t!+n ;+"4ort! ?or prep+r+tion o? ino$ul+. ;e
+lo t!+n0 /iolo'i$+l *er@i$e P+$ilit2 t+?? ?or +nim+l $+re +n" 8+2 Youn' ?or
prep+r+tion o? ?i'ure. 1!i 4or0 4+ ?un"e" b2 t!e .6 Me"i$+l 8ee+r$! (oun$il
(M8().
Author $ontributions
(on$ei@e" +n" "ei'ne" t!e eLperiment: *3. Per?orme" t!e eLperiment: *A -G A;
MP"eM *3. An+l2<e" t!e "+t+: */ HH *3. ;rote t!e p+per: *3 -(.
eferences
1. 1. (ollin'e - (2001) Prion "ie+e o? !um+n +n" +nim+l: t!eir $+ue +n"
mole$ul+r b+i. Ann 8e@ 5euro$i 2>: 519550. "oi:
10.11>6&+nnure@.neuro.2>.1.519.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
2. 2. /ueler H, A'u<7. "oi: 10.1016&00927
867>(9%)90%607%.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
3. %. Pi$!er M, 8uli$0e 1, 8+eber A, *+iler A, Moer M, et +l. (1996) Prion protein
(PrP) 4it! +mino7proLim+l "eletion retorin' u$eptibilit2 o? PrP 0no$0out mi$e
to $r+pie. :M/E - 15: 1255126>. "oi: 10.109%&emboM&16.20.6057.
o (ro8e?
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4. >. Moore 8(, Hope -, M$/ri"e PA, M$(onnell ), *el?ri"'e -, et +l. (1998) Mi$e
4it! 'ene t+r'ette" prion protein +lter+tion !o4 t!+t Prnp2 S"n# +n" Prn" +re
$on'ruent. 5+t Genet 18: 118125. "oi: 10.10%8&n'02987118.
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5. 5. ;et+4+2 #, Goo"m+n PA, Miren"+ (A, M$6inle2 MP, (+rlon GA, et +l.
(1987) #itin$t prion protein in !ort +n" lon' $r+pie in$ub+tion perio" mi$e.
(ell 51: 651662. "oi: 10.1016&00927867>(87)901%>76.
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6. 6. (+rlon GA, Goo"m+n PA, 3o@ett M, 1+2lor /A, M+r!+ll *1, et +l. (1988)
Geneti$ +n" pol2morp!im o? t!e moue prion 'ene $ompleL: $ontrol o? $r+pie
in$ub+tion time. Mol (ell /iol 8: 552855>0.
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7. 7. (+rlon GA, :belin' (, 1or$!i+ M, ;et+4+2 #, Pruiner */ (199%)
#elimitin' t!e 3o$+tion o? t!e *$r+pie Prion )n$ub+tion 1ime Gene on
(!romoome 2 o? t!e Moue. Geneti$ 1%%: 979988.
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o Goo'le *$!ol+r
8. 8. 3lo2" *, 1!ompon *8, /e$0 -, 3ine!+n -, ;+"4ort! -#, et +l. (200>)
)"enti?i$+tion +n" $!+r+$teri<+tion o? + no@el moue prion 'ene +llele. M+mm
Genome 15: %8%%89. "oi: 10.1007&00%%5700>7%0>175.
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9. 9. (ollin'e -, P+lmer M*, #r2"en A- (1991) Geneti$ pre"ipoition to i+tro'eni$
(reut<?el"t7-+0ob "ie+e. 3+n$et %%7: 1>>11>>2. "oi: 10.1016&01>07
67%6(91)9%1287=.
o (ro8e?
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o Goo'le *$!ol+r
10.10. Me+" *, *tump? MP, ;!it?iel" -, /e$0 -, Poulter M, et +l. (200%) /+l+n$in'
ele$tion +t t!e prion protein 'ene $onitent 4it! pre!itori$ 0uru7li0e epi"emi$.
*$ien$e %00: 6>06>%. "oi: 10.1126&$ien$e.108%%20.
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11.11. P+lmer M*, #r2"en A-, Hu'!e -1, (ollin'e - (1991) Homo<2'ou prion
protein 'enot2pe pre"ipoe to por+"i$ (reut<?el"t7-+0ob "ie+e. 5+ture %52:
%>0%>2. "oi: 10.10%8&%52%>0+0.
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12.12. (ollin'e - (2005) Mole$ul+r neurolo'2 o? prion "ie+e. - 5eurol 5eurour'
P2$!i+tr2 76: 906919. "oi: 10.11%6&Mnnp.200>.0>8660.
o (ro8e?
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o Goo'le *$!ol+r
13.1%. Me+" *, Poulter M, .p!ill -, /e$0 -, ;!it?iel" -, et +l. (2009) Geneti$ ri0
?+$tor ?or @+ri+nt (reut<?el"t7-+0ob "ie+e: + 'enome74i"e +o$i+tion tu"2.
3+n$et 5eurol 8: 5766. "oi: 10.1016&*1>7>7>>22(08)7026575.
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14.1>. 3lo2" *, (ollin'e - (2005) Geneti$ *u$eptibilit2 to Prion #ie+e in
Hum+n +n" Mi$e. (urrent Genomi$ 6: 111. "oi: 10.217>&1%8920205%202166.
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o Goo'le *$!ol+r
15.15. 3lo2" *, En4u+<or E5, /e$0 -, M+llinon G, P+rr+ll M, et +l. (2001)
)"enti?i$+tion o? multiple Du+ntit+ti@e tr+it lo$i lin0e" to prion "ie+e in$ub+tion
perio" in mi$e. Pro$ 5+tl A$+" *$i .*A 98: 6279628%. "oi:
10.107%&pn+.1011%0%98.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
16.16. 3lo2" *, .p!ill -/, 1+r'on0i P=, Pi!er :, (ollin'e - (2002) )"enti?i$+tion o?
'eneti$ lo$i +??e$tin' moue7+"+pte" bo@ine pon'i?orm en$ep!+lop+t!2
in$ub+tion time in mi$e. 5euro'eneti$ >: 7781. "oi: 10.1007&100>87002701%%7
9.
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o Goo'le *$!ol+r
17.17. *tep!enon #A, (!iotti 6, :belin' (, Grot! #, #eArmon" *-, et +l. (2000)
Ou+ntit+ti@e tr+it lo$i +??e$tin' prion in$ub+tion time in mi$e. Genomi$ 69: >7
5%. "oi: 10.1006&'eno.2000.6%20.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
18.18. M+nol+0ou 6, /e+ton -, M$(onnell ), P+rDu+r (, M+non -, et +l. (2001)
Geneti$ +n" en@ironment+l ?+$tor mo"i?2 bo@ine pon'i?orm en$ep!+lop+t!2
in$ub+tion perio" in mi$e. Pro$ 5+tl A$+" *$i .*A 98: 7>027>07. "oi:
10.107%&pn+.121172098.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
19. 19. Moreno (8, 3+ntier P, 3+ntier ), *+rr+"in P, :len -M (200%) #ete$tion o?
ne4 Du+ntit+ti@e tr+it lo$i ?or u$eptibilit2 to tr+nmiible pon'i?orm
en$ep!+lop+t!ie in mi$e. Geneti$ 165: 20852091.
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o Goo'le *$!ol+r
20.20. Me+" *, .p!ill -, /e$0 -, Poulter M, (+mpbell 1, et +l. (2011) Genome74i"e
+o$i+tion tu"2 in multiple !um+n prion "ie+e u''et 'eneti$ ri0 ?+$tor
+""ition+l to P85P. Hum Mol Genet 21: 18971906. "oi: 10.109%&!m'&""r607.
o (ro8e?
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o Goo'le *$!ol+r
21.21. 1+m'une2 G, Gile 6, Gli""en #=, 3e+r" P, ;ille H, et +l. (2008) Gene
$ontributin' to prion p+t!o'enei. - Gen =irol 89: 17771788. "oi:
10.1099&@ir.0.2008&00125570.
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o Goo'le *$!ol+r
22.22. 3lo2" *:, M+2t!+m :G, Pot+ H, Gri<en0o@+ -, Molou :, et +l. (2009)
H:(1#2 i +o$i+te" 4it! u$eptibilit2 to moue +n" !um+n prion "ie+e.
P3o* Genet 5: e1000%8%. "oi: 10.1%71&Mourn+l.p'en.1000%8%.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
23.2%. 3lo2" *:, M+2t!+m :G, Gri<en0o@+ -, Hummeri$! H, (ollin'e - (2010) A
(opine ?+mil2 member, (pne8, i + $+n"i"+te Du+ntit+ti@e tr+it 'ene ?or prion
"ie+e in$ub+tion time in moue. 5euro'eneti$ 11: 185191. "oi:
10.1007&100>870097021978.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
24.2>. =+l"+r ;, *olber' 3(, G+u'uier #, /urnett *, 6lenerm+n P, et +l. (2006)
Genome74i"e 'eneti$ +o$i+tion o? $ompleL tr+it in !etero'eneou to$0 mi$e.
5+t Genet %8: 879887. "oi: 10.10%8&n'18>0.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
25.25. Gri<en0o@+ -, A0!t+r *, (ollin'e -, 3lo2" *: (2010) 1!e retinoi$ A$i"
re$eptor /et+ (r+rb) re'ion o? mmu1> i +o$i+te" 4it! prion "ie+e in$ub+tion
time in moue. P3o* E5: 5: e15019. "oi: 10.1%71&Mourn+l.pone.0015019.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
26.26. 6il0enn2 (, /ro4ne ;-, (ut!ill )(, :meron M, Altm+n #G (2010)
)mpro@in' /io$ien$e 8ee+r$! 8eportin': 1!e A88)=: Gui"eline ?or
8eportin' Anim+l 8ee+r$!. Plo* /iolo'2 8: e1000>12. "oi:
10.1%71&Mourn+l.pbio.1000>12.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
27.27. M+t<u0 MM, #ionne 3, Guo O^, 6um+r 18, 3ebo@it< 8M (1998) E@+ri+n
?un$tion in uperoLi"e "imut+e 1 +n" 2 0no$0out mi$e. :n"o$rinolo'2 1%9:
>008>011. "oi: 10.1210&en.1%9.9.>008.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
28.28. Gri<en0o@+ -, A0!t+r *, Hummeri$! H, 1omlinon A, A+nte :A, et +l. (2012)
E@ereLpreion o? t!e Hp+1% (*t$!) 'ene re"u$e prion "ie+e in$ub+tion time
in mi$e. Pro$ 5+tl A$+" *$i .*A 109: 1%7221%727. "oi:
10.107%&pn+.1208917109.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
29.29. EX*!e+ M, M+2t!+m :G, 3ine!+n -M, /r+n"ner *, (ollin'e -, et +l. (2008)
)n@eti'+tion o? M$p1 + + Ou+ntit+ti@e 1r+it Gene ?or Prion #ie+e )n$ub+tion
1ime in Moue. Geneti$ 180: 559566. "oi: 10.15%>&'eneti$.108.09089>.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
30.%0. ;+"4ort! -#, -oiner *, Hill AP, (+mpbell 1A, #ebrul+i M, et +l. (2001)
1iue "itribution o? prote+e reit+nt prion protein in @+ri+nt (-# uin' +
!i'!l2 eniti@e immuno7blottin' ++2. 3+n$et %58: 171180. "oi:
10.1016&*01>0767%6(01)05>0%7>.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
31.%1. A+nte :, 3ine!+n -, #ebrul+i M, -oiner *, Go4l+n" ), et +l. (2002) /*:
prion prop+'+te + eit!er @+ri+nt (-#7li0e or por+"i$ (-#7li0e prion tr+in in
tr+n'eni$ mi$e eLprein' !um+n prion protein. :M/E - 21 (2%): 6%586%66.
"oi: 10.109%&emboM&$"?65%.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
32.%2. ;+"4ort! -#, -oiner *, 3ine!+n -, (ooper *, Po4ell (, et +l. (2006)
P!enot2pi$ !etero'eneit2 in in!erite" prion "ie+e (P1023) i +o$i+te" 4it!
"i??erenti+l prop+'+tion o? prote+e7reit+nt 4il"7t2pe +n" mut+nt prion protein.
/r+in 129: 15571569. "oi: 10.109%&br+in&+4l076.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
%%. %%. Hit<em+nn /, #+in 6, 6+ne *, Hit<em+nn 8 (199>) Purt!er7*tu"ie on t!e
8el+tion!ip /et4een #op+mine (ell7#enit2 +n" H+loperi"ol7)n"u$e"
(+t+lep2. - P!+rm :Lp 1!er 271: 969976.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
34.%>. 3lo2" *, 3ine!+n -, #ebrul+i M, -oiner *, /u$0ell -, et +l. (200>)
(!+r+$teri<+tion o? t4o "itin$t prion tr+in "eri@e" ?rom bo@ine pon'i?orm
en$ep!+lop+t!2 tr+nmiion to inbre" mi$e. - Gen =irol 85: 2>712>78. "oi:
10.1099&@ir.0.7988970.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
35.%5. P+r0in :1, ;+tt 51, Hu+in ), :$0m+n :A, :$0m+n (/, et +l. (2007)
(ellul+r prion protein re'ul+te bet+7e$ret+e $le+@+'e o? t!e Al<!eimerX
+m2loi" pre$uror protein. Pro$ 5+tl A$+" *$i .*A 10>: 1106211067. "oi:
10.107%&pn+.060962110>.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
36.%6. 3+uren -, Gimbel #A, 52'++r" H/, Gilbert -;, *trittm+tter *M (2009)
(ellul+r prion protein me"i+te imp+irment o? 2n+pti$ pl+ti$it2 b2 +m2loi"7bet+
oli'omer. 5+ture >57: 112811%2. "oi: 10.10%8&n+ture07761.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
37.%7. /+rr2 A:, 6l2ubin ), M$ #on+l" -M, M+bl2 A-, P+rrell MA, et +l. (2011)
Al<!eimerX #ie+e /r+in7#eri@e" Am2loi"7bet+7Me"i+te" )n!ibition o? 31P )n
=i@o ) Pre@ente" b2 )mmunot+r'etin' (ellul+r Prion Protein. - 5euro$i %1:
7259726%. "oi: 10.152%&-5:.8E*().6500710.2011.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
38.%8. Preir #/, 5i$oll A-, 6l2ubin ), P+ni$o *, M$ #on+l" -M, et +l. (2011)
)nter+$tion bet4een prion protein +n" toLi$ +m2loi" bet+ +emblie $+n be
t!er+peuti$+ll2 t+r'ete" +t multiple ite. 5+t (ommun 2: %%6. "oi:
10.10%8&n$omm1%>1.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
39.%9. *$!ult< -, *$!4+r< A, 5ei"!ol" *, /ur4in0el M, 8iemer (, et +l. (200>) 8ole
o? interleu0in71 in prion "ie+e7+o$i+te" +tro$2te +$ti@+tion. Am - P+t!ol 165:
671678. "oi: 10.1016&*000279>>0(10)6%%%177.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
40.>0. -o2$e P), Pr+tt+ P, Pi!er :M(, A$e@e"o7Aro<en+ A (2011) *E#1 +n" 1#P7
>% +nim+l mo"el o? +m2otrop!i$ l+ter+l $leroi: re$ent +"@+n$e in
un"ert+n"in' "ie+e to4+r" t!e "e@elopment o? $lini$+l tre+tment. M+mm
Genome 22: >20>>8. "oi: 10.1007&00%%5701179%%971.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
41.>1. Mur+0+mi 6, Mur+t+ 5, 5o"+ Y, 1+!+r+ *, 6+ne0o 1, et +l. (2011) *E#1
((opper&Ain$ *uperoLi"e #imut+e) #e?i$ien$2 #ri@e Am2loi" bet+ Protein
Eli'omeri<+tion +n" Memor2 3o in Moue Mo"el o? Al<!eimer #ie+e. - /iol
(!em 286: >>557>>568. "oi: 10.107>&Mb$.M111.279208.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
>2. >2. )+"e$ol+ (, A!+n' P, 5i4+ 6, :$0m+n (, 1urner *6, et +l. (1999) *E#1
re$ue $erebr+l en"ot!eli+l "2?un$tion in mi$e o@ereLprein' +m2loi"
pre$uror protein. 5+t 5euro$i 2: 157161.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
43.>%. 3ee #;, *o!n HE, 3im H/, 3ee YG, 6im Y*, et +l. (1999) Alter+tion o? ?ree
r+"i$+l met+bolim in t!e br+in o? mi$e in?e$te" 4it! $r+pie +'ent. Pree 8+"i$
8e %0: >99507. "oi: 10.1080&10715769900%005>1.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
44.>>. *i0o@+ A, M+!+" #-, Pu"ne2 (, (+mpbell G, (+"o'+n M, et +l. (2010)
Morp!olo'i$+l +n" Pun$tion+l Abnorm+litie in Mito$!on"ri+ Ao$i+te" 4it!
*2n+pti$ #e'ener+tion in Prion #ie+e. Am - P+t!ol 177: 1>111>21. "oi:
10.2%5%&+Mp+t!.2010.0910%7.
o (ro8e?
o PubMe"&5(/)
o Goo'le *$!ol+r
45.>5. PreiLe M, 8o"ri'ue< A, #+l?o :, Perrer ) (2005) ELi"+tion, 'l2$oLi"+tion,
lipoLi"+tion, nitr+tion, +n" repone to oLi"+ti@e tre in t!e $erebr+l $orteL in
(reut<?el"t7-+0ob "ie+e. 5eurobiol A'in' 27: 18071815. "oi:
10.1016&M.neurobiol+'in'.2005.10.006.
Jurnal I
(urr Genomi$. 2012 Au'ut; 1%(5): %69%78.
Publi!e" online 2012 Au'ut. "oi: 10.217>&1%892021280161922%
PM()#: PM(%>0189>
3unctional Genomics Approach for
Identification of *olecular Processes
#nderlying Neurodegenerati7e "isorders
in Prion "iseases
.rmil+ /+u,
1,B
3e 3uo Gu+n,
1
+n" *tep!en * Moore
2
Go to:
Abstract
Prion "ie+e or tr+nmiible pon'i?orm en$ep!+lop+t!ie (1*:) +re in?e$tiou
neuro"e'ener+ti@e "ior"er le+"in' to "e+t!. 1!ee in$lu"e (reut<?el"t7-+0ob "ie+e
((-#), ?+mili+l, por+"i$ +n" @+ri+nt (-# +n" 0uru in !um+n; +n" +nim+l 1*: in$lu"e
$r+pie in !eep, bo@ine pon'i?orm en$ep!+lop+t!2 (/*:) in $+ttle, $!roni$ 4+tin'
"ie+e ((;#) o? mule "eer +n" el0, +n" tr+nmiible min0 en$ep!+lop+t!2. All t!ee
1*: !+re $ommon p+t!olo'i$+l ?e+ture u$! + +$$umul+tion o? mi7?ol"e" prion
protein in t!e $entr+l ner@ou 2tem le+"in' to $ellul+r "2?un$tion +n" $ell "e+t!. )t i
import+nt to $!+r+$teri<e t!e mole$ul+r p+t!4+2 +n" e@ent le+"in' to prion in"u$e"
neuro"e'ener+tion. Here 4e "i$u t!e imp+$t o? t!e ?un$tion+l 'enomi$ +ppro+$!e
in$lu"in' mi$ro+rr+2, ubtr+$ti@e !2bri"i<+tion +n" mi$ro85A pro?ilin' in elu$i"+tin'
tr+n$ription+l $+$+"e +t "i??erent t+'e o? "ie+e. M+n2 o? t!ee tr+n$ription+l
$!+n'e !+@e been ober@e" in multiple neuro"e'ener+ti@e "ie+e 4!i$! m+2 +i" in
i"enti?i$+tion o? biom+r0er ?or "ie+e. A $ompre!eni@e $!+r+$teri<+tion o? eLpreion
pro?ile impli$+te" in neuro"e'ener+ti@e "ior"er 4ill un"oubte"l2 +"@+n$e our
un"ert+n"in' on neurop+t!olo'2 +n" "2?un$tion "urin' prion "ie+e +n" ot!er
neuro"e'ener+ti@e "ior"er. ;e +lo preent +n outloo0 on t!e ?uture 4or0 4!i$! m+2
?o$u on +n+l2i o? tru$tur+l 'eneti$ @+ri+tion, 'enome +n" tr+n$riptome eDuen$in'
uin' neLt 'ener+tion eDuen$in' 4it! +n inte'r+te" +ppro+$! on +nim+l +n" !um+n 1*:
rel+te" tu"ie.
/eywords4 Prion, 1*:, 'ene eLpreion, ?un$tion+l $+n"i+te 'ene, P85P, mi$ro+rr+2.
Go to:
1)INT!"#$TI!N
Prion "ie+e, or tr+nmiible pon'i?orm en$ep!+lop+t!ie (1*:), +re in@+ri+bl2 ?+t+l
neuro"e'ener+ti@e "ior"er +??e$tin' bot! !um+n +n" +nim+l. Hum+n prion "ie+e
in$lu"e 6uru, (reut<?el"t7-+0ob "ie+e ((-#) ?or +bout 85U o? t!e $+e, ?+mili+l (-#
in 10715U o? t!e $+e +n" @+ri+nt (-# 4!i$! i limite" to t!e .6 +n" Pr+n$e I1, 2J.
Anim+l 1*: (1+ble 1 1) in$lu"e $r+pie in !eep, bo@ine pon'i?orm en$ep!+lop+t!2
(/*:) in $+ttle, $!roni$ 4+tin' "ie+e ((;#) in $er@i", tr+nmiible min0
en$ep!+lop+t!2 in min0, +n" ?eline pon'i?orm en$ep!+lop+t!2 (P*:) in $+t, +n" eLoti$
un'ul+te pon'i?orm en$ep!+lop+t!2 (:.:) o? $+pti@e 4il" rumin+nt I%J. Anim+l
+??e$te" b2 1*: in$re+e t!e ri0 o? tr+nmiion to !um+n + 4ell + erioul2 "e$line
t!e ?+rm +nim+l pro"u$tion I>J. Por eL+mple, in$e t!e /*: epi"emi$ in 1986,
l+u'!terin' o? million o? $+ttle +n" import b+n on t!e bee? !+@e reulte" in ubt+nti+l
loe. Prion "ie+e o$$ur + por+"i$, 'eneti$, +n" tr+nmiible "ie+e, !o4e@er,
por+"i$ +n" !erit+ble ?orm o? t!e "ie+e +re more ?reDuent.
1+ble 1.
1r+nmiible *pon'i?orm :n$ep!+lop+t!ie (Prion #ie+e) in Hum+n +n" Anim+l
)n'etion o? $ont+min+te" biolo'i$+l m+teri+l @i+ ?oo" reulte" in t!e +$Duire" ?orm o?
"ie+e e.'., 6uru 4+ t!e ?irt 0no4n !um+n 1*: "ue to ritu+liti$ $+nnib+lim I5J.
/*: i +not!er m+i@e $ommon7our$e epi"emi$ $+ue" b2 me+t +n" bone me+l ?e"
prim+ril2 to "+ir2 $o4 I6, 7J +n" more re$entl2 @(-# in !um+n !+ been +o$i+te" 4it!
eLpoure to t!e /*: +'ent I1J. En t!e ot!er !+n", mut+tion in t!e norm+l prion protein
en$o"e" b2 t!e P8io5 Protein (P85P) 'ene, +re lin0e" to 'eneti$+ll2 in!erite" prion
"ie+e in$lu"in' Gertm+nn7*tr+uler7*!ein0er (G**) "ie+e, ?+t+l ?+mili+l inomni+
(PP)) +n" 'eneti$+ll2 +o$i+te" (-# I2, >J.
Go to:
6)PAT+!G%N%&I& !3 PI!N "I&%A&%
)n m+mm+l, t!e $on@erion o? t!e norm+l, $ellul+r io?orm o? t!e prion protein (PrP
(
) to
t!e "ie+e7$+uin' io?orm (PrP
*$
) i t!e 0e2 pro$e un"erl2in' prion "ie+e. PrP
(
+n"
PrP
*$
!+@e "itin$t $on?orm+tion 4it! PrP
(
!+ eLteni@e w7!eli$+l $ontent 4!ere+ PrP
*$
i ri$! in m7!eet tru$ture 4it! le w7!eli$+l $ontent I8, 9J, !+ t!e propenit2 to
+''re'+te +n" !+ t!e reit+n$e to proteol2i I10J. Prion "ie+e in +nim+l $+n be
$!+r+$teri<e" b2 PrP
*$
repli$+tion +n" +$$umul+tion, pon'i?orm @+$uol+tion +n"
+tro$2ti$ 'lioi, 2n+pti$ "e'ener+tion le+"in' to neuro"e'ener+tion +n" let!+lit2 I11J
4!ile t!ee 2mptom +re $ommon in m+n2 neuro"e'ener+ti@e "ior"er I5, 12J.
ApproLim+tel2 >5U o? t!e PrP( protein i w7!eli$+l 4it! t4o @er2 !ort tret$!e o? m7
!eet +n" it $on@erion to PrP*$ reult in protein 4it! v%0U w7!eliL +n" >5U m7!eet.
Et!er +n$ill+r2 protein +re +lo in@ol@e" in t!i $on@erion pro$e +n" PrP$ +ppe+r to
bin" to PrP*$ to ?orm +n interme"i+te $ompleL I1%J. 1!e m+Mor route o? tr+nmiion ?or
m+n2 1*: i t!rou'! or+l in?e$tion +?ter 4!i$! prion pre+" t!rou'! t!e 'ut to
e$on"+r2 immune tiue +n" t!en to t!e br+in I5J. Purt!ermore, prion !+@e been
"ete$te" in "i??erent l2mp!oi" or'+n in$lu"in' t!e pleen, l2mp! no"e, Pe2erX p+t$!e
+n" tonil I1>716J.
Prion protein (PrP) i en$o"e" b2 + $!romoom+l 'ene, PRNP2 4it! + in'le eLon ?or t!e
PrP open re+"in' ?r+me +lt!ou'! t!e 'ene itel? $omprie o? t4o to t!ree eLon I17720J.
1!e ot!er eLon o? t!e P85P 'ene $ont+in untr+nl+te" eDuen$e in$lu"in' t!e promoter
+n" termin+tion ite 4it! multiple $opie o? G(7ri$! repe+t in t!e PrP promoter I21J.
(omp+rion o? + tot+l o? 9%7 PRNP eDuen$e ?rom 8% pe$ie u''ete" + tri0in'
"e'ree o? $oner@+tion +mon' t!e m+mm+li+n eDuen$e I22J. Ho4e@er, @+ri+tion in
PrP eDuen$e eLit bot! bet4een pe$ie +n" bet4een in"i@i"u+l 4it!in pe$ie 're+tl2
+??e$tin' u$eptibilit2 to prion in?e$tion I2%J. )n$re+in' e@i"en$e u''et t!+t ot!er
'ene in +""ition to t!e P85P 'ene +lo $ontribute to t!e 'eneti$ u$eptibilit2 o?
+$Duire" 1*:, t!u t!ere i + nee" to impro@e our un"ert+n"in' o? t!e mole$ul+r
me$!+nim un"erl2in' prion "ie+e p+t!o'enei. Genome74i"e tu"ie in $+ttle I2>7
28J, !eep I29, %0J, mi$e I%1, %2J, +n" !um+n I%%J !+@e i"enti?ie" 'enomi$ re'ion +n"
poition+l $+n"i"+te 'ene, ot!er t!+n t!e prion 'ene, in@ol@e" in 1*: p+t!o'enei. 1!i
re@ie4 !i'!li'!t t!e re$ent +"@+n$e in t!e ?iel" o? prion "ie+e in !um+n, moue
mo"el +n" rumin+nt pe$ie to un"ert+n" t!e $ompleLitie o? mole$ul+r p+t!4+2 uin'
!i'! t!rou'!put ?un$tion+l 'enomi$ te$!nolo'ie.
Go to:
;)+IG+ T+!#GP#T G%N% %JP%&&I!N
&T#"I%& A&&!$IAT%" 5IT+ +#*AN PI!N
"I&%A&%&
1!e PRNP 'ene "etermine bot! u$eptibilit2 +n" p!enot2pe o? prion "ie+e in
!um+n, 4it! point mut+tion le+"in' to + pe$i?i$ p+t!olo'i$+l p!enot2pe I%>, %5J. A
'enome74i"e tu"2 in p+tient 4it! @+riou ?orm o? prion "ie+e (@+ri+nt, por+"i$,
i+tro'eni$ (-# +n" 0uru p+tient) $on?irme" t!+t t!e ri0 o? "e@elopin' prion "ie+e i
tron'l2 +o$i+te" 4it! t!e pol2morp!i$ $o"on 129 o? t!e PRNP 'ene I%%J. Preen$e o?
in'le nu$leoti"e pol2morp!im (*5P) in t!e intron o? PRNP, retinoi$ +$i" re$eptor7m
protein =RARB>, +n" *(G10&t+t!min7li0e 2, + neuron+l 'ro4t!7+o$i+te" protein
(STMN2) in$re+e" t!e ri0 o? prion "ie+e. 8etinoi$ +$i" i 0no4n to re'ul+te t!e
eLpreion o? t!e prion protein in $ell $ulture I%6J, +n" *(G10 mo"ul+te mi$rotubule
t+bilit2 in neuron+l $ell, 4!i$!, in turn, mi'!t potenti+ll2 mo"ul+te prion neurotoLi$it2
I%7J in"i$+tin' t!e in@ol@ement o? t!ee 'ene in t!e p+t!o'enei o? prion "ie+e.
#i??erent +ppro+$!e in$lu"in' !um+n 'enome 4i"e +o$i+tion tu"ie (G;A*), moue
m+ppin' +n" "i??erenti+l eLpreion tu"ie !+@e u''ete" t!e +o$i+tion o? *!+"oo
(*!o, !+"o4 o? prion protein)(*P85) +n" :% ubiDuitin li'+e (H:(1#2) 4it! ri0 o?
por+"i$ +n" @+ri+nt (-# I%87>0J. *!+"oo i + neuron+ll2 eLpree" 'l2$oprotein o?
un0no4n ?un$tion. #ue to + $oner@e" p!2iolo'i$+l +$ti@it2 bet4een PrP
(
+n" *!o, it
mi'!t be +$tin' on imil+r i'n+lin' p+t!4+2 in !um+n prion p+t!obiolo'2 I>1J. /2
!omolo'2, H:(1#2 i +n :% ubiDuitin li'+e +n" i in@ol@e" in t!e ubiDuitin2l+tion o?
protein ?or t+r'ete" "e'r+"+tion b2 t!e prote+ome I>0J. 1!e ubiDuitin7proteoome
2tem !+ +lo been impli$+te" in prion "ie+e +n" + number o? ot!er
neuro"e'ener+ti@e "ior"er I>0J.
)n +not!er tu"2 I>2J, mi$ro+rr+2 +n+l2i o? t!e ?ront+l $orteL o? 15 p+tient 4it!
por+"i$ (-# re@e+le" t!e in@ol@ement o? 79 up7re'ul+te" (e.'., met+llot!ionein71 +n" 2)
+n" 275 "o4n7re'ul+te" 'ene (e.'., *2n+ptoom+l7+o$i+te" protein 25 (*5AP25)
mo"ul+tin' 2n+pti$ ?un$tion +n" pl+ti$it2) $omp+re" to !e+lt!2 $ontrol.
Met+llot!ionein71 +n" 72 +re $2teine7ri$! intr+$ellul+r protein 4it! + !i'! $+p+$it2 to
bin" to <in$ +n" $opper ion +n" +re 0no4n to be m+inl2 preent in t!e $2topl+m o?
+tro$2te o? t!e $erebr+l $orteL +n" 4!ite m+tter I>%J. Altere" eLpreion o? 'ene
in@ol@e" in met+l ion bin"in' +$ti@it2 4oul" u''et +n +berr+nt ion !omeot+i in (-#
I>2J. *5AP725 i in@ol@e" in mo"ul+tin' 2n+pti$ ?un$tion +n" pl+ti$it2 +n" t!e
2n+pti$ imp+irment i + m+Mor p+t!olo'i$+l me$!+nim o? (-# I>>J. Purt!er
$!+r+$teri<+tion o? t!ee 'ene i $ru$i+l to un"ert+n"in' t!e mole$ul+r b+i o?
p+t!olo'i$+l pro$e o? prion "ie+e.
Go to:
@)I"%NTI3I$ATI!N !3 $AN"I"AT% G%N%&
T+!#G+ 3#N$TI!NA' G%N!*I$ &T#"I%& IN
ANI*A' P!T%IN "I&%A&%&
)t !+ been 4ell "o$umente" t!+t bei"e P85P, ot!er 'ene +re +lo in@ol@e" in t!e
p+t!o'enei o? prion "ie+e I>5J. 3+r'e $+le 'ene eLpreion pro?ilin' o? in?e$te" @.
$ontrol +nim+l to i"enti?2 "i??erenti+ll2 eLpree" (#:) 'ene m+2 !elp in un"ert+n"in'
no@el 'ene +n" p+t!4+2 t!+t +re 4it$!e" on +n" o?? +t @+riou time point "urin' t!e
p+t!o'enei o? prion "ie+e. #i??erent ?un$tion+l 'enomi$ te$!nolo'ie !+@e been
ue" to "ete$te" "i??erenti+l 'ene eLpreion in$lu"in' $#5A libr+rie I>6J, m85A
"i??erenti+l "ipl+2 I>7J, uppreion ubtr+$ti@e !2bri"i<+tion I>8J, mi$ro+rr+2 I>975>J
+n" more re$entl2 neLt 'ener+tion eDuen$in' I55J. 1!ee tu"ie in eLperiment+l +nim+l
mo"el or ?rom $lini$+ll27in?e$te" +nim+l !+@e re@e+le" multiple 'ene +n" i'n+lin'
p+t!4+2 t!+t m+2 be in@ol@e" in 1*: p+t!o'enei.
@)1) Prion elated Gene %8pression $hanges in Animal *odels
#ue to t!e +@+il+bilit2 o? limite" m+teri+l ?rom prion7in?e$te" +mple +t pre7$lini$+l +n"
$lini$+l t+'e ?or !um+n +n" ot!er +nim+l; +n" "ue to t!e imil+ritie bet4een t!e
moue +n" !um+n 'enome, t!e moue mo"el !+@e been ue" in e@er+l prion
p+t!o'enei tu"ie. 1!ee mo"el !+@e pro@i"e" t!e number +n" repli$+tion reDuire"
?or "ei'nin' l+r'e $+le tu"ie to i"enti?2 t!e 'ene o? interet +t "i??erent time point
t!rou'!out "ie+e p+t!o'enei I56J. Purt!ermore, moue mo"el $+n +lo be ue" ?or
tetin' t!e $+n"i"+te 'ene ?rom o@er7eLprein' tr+n'eni$ to 0no$0out, to "etermine
t!eir e??e$t on prion p+t!olo'2.
)n br+in tiue ?rom eLperiment+l $r+pie7in?e$tion +nim+l mo"el (1+ble 6 6 pro@i"e +
lit o? !i'! t!rou'!put tu"ie $on"u$te" in moue mo"el), "i??erenti+ll2 eLpree" (#:)
'ene !+@e been i"enti?ie" +t "i??erent t+'e o? prion "ie+e uin' mi$ro+rr+2 +n+l2i
I>7, 57760J. 1!e 'lob+l +n+l2i o? t!e o@er+ll tr+n$ription+l repone in pre7$lini$+l +n"
$lini$+l $entr+l ner@ou 2tem tiue o? mi$e in repone to prion in?e$tion re@e+le" t!+t
m+n2 o? t!e in"i@i"u+l 'ene i"enti?ie" !+" +n +o$i+tion 4it! t!e neuro"e'ener+ti@e
pro$e in prion "ie+e + 4ell + Al<!eimerN "ie+e (A#) I57J. 1!e "i??erenti+l
eLpreion o? 'ene in@ol@e" in $ellul+r tre (oLi"+ti@e tre +n" :8 tre), +$ti@+te"
:8 +n" mito$!on"ri+l +poptoti$ p+t!4+2, prote+e in!ibitor, $+l$ium bin"in' protein,
en"oome&l2oome ?un$tion, immunit2, 2n+pe ?un$tion, met+l ion bin"in', +n"
+$ti@+te" $!oleterol bio2nt!ei, !+@e been !o4n in t!e $r+pie7in?e$te" !ippo$+mpu
I58J +n" br+in I59, 60J. Purt!ermore, +ll t!ee tu"ie !+@e in"i$+te" imil+ritie bet4een
'ene eLpreion p+ttern ?oun" in br+in +??e$te" b2 A# +n" +'in', repe$ti@el2.
1+ble 2.
Hi'! 1!rou'!put Gene :Lpreion *tu"ie in #i??erent 1iue ?rom Prion7in?e$te"
Moue Mo"el 3e+"in' to t!e )"enti?i$+tion o? M+Mor Pun$tion+l (+n"i"+te Gene &
M+r0er & P+t!4+2
1!e "i??erenti+l eLpreion o? t!e 'ene in@ol@e" in immunit2, protein ?ol"in',
ubiDuitin&proteoome or in t!e en"oome&l2oome 2tem 4+ ober@e" in t!e br+in +n"
t!e pleen in $r+pie7in?e$te" mi$e prior to t!e onet o? $lini$+l 2mptom I61J. Altere"
eLpreion o? ?our 'ene, A1P+e, 5+[&6[ tr+nportin', bet+ 1 pol2pepti"e (Atp1b1),
Gro4t! !ormone (G!), +$i"i$ leu$ine7ri$! nu$le+r p!op!oprotein %2 ?+mil2 member A
(Anp%2+) +n" Gr+nulin (Grn) +t t!e @er2 e+rl2 time o? pot7in?e$tion pro@i"e" ini'!t
into t!e me$!+nim o? p+t!o'enei I61J. H4+n' &$ '!+ I62J per?orme" + "et+ile"
$!+r+$teri<+tion uin' t4o prion tr+in, "i??erent in$ub+tion time, +n" mi$e ?rom iL
"i??erent 'eneti$ b+$0'roun" +n" i"enti?ie" + $ore o? %%% 'ene $entr+l to prion "ie+e
t!+t 4ere "i??erenti+ll2 eLpree" in +ll ?i@e o? t!e $ombin+tion in@ol@in' mi$e 4it!
norm+l le@el o? prion protein. 1r+n$ription+l +n+l2i o? ?olli$ul+r "en"riti$ $ell +n"
m+$rop!+'e enri$!e" pleni$ $ell re@e+le" t!e 'ene rel+te" to iron met+bolim +n"
!omeot+i + t!e m+Mor p+t!4+2 I6%J. Genome 4i"e eLpreion tu"2 in mi$e
ino$ul+te" 4it! /*: !omo'en+te in"i$+te" $!+n'e in t4o m+in biolo'i$+l pro$ee,
neur+l $ell met+bolim +n" "e?ene me$!+nim I6>J. *ome o? t!e 'ene i"enti?ie" in
t!ee tu"ie m+2 er@e + m+r0er ?or prion "ie+e "i+'noi 4!i$! $oul" be put+ti@e
$+n"i"+te ?or "ru' t!er+pie.
@)6) Prion elated Gene %8pression in uminants
Gene eLpreion pro?ilin' tu"ie in n+tur+l t+r'et rumin+nt pe$ie ($+ttle, !eep,
el0&"eer) in?e$te" b2 n+tur+l route (or+l in?e$tion) +re import+nt ?or un"ert+n"in' t!e
p+t!o'enei o? t!e prion "ie+e. )n $+ttle, or+ll2 in?e$te" 4it! /*: +'ent (12 +n" >5
mont! pot7in?e$tion), 101 #: 'ene in Pe2erX p+t$! tiue I52J +n" 176 #: 'ene in
me"ull+ I5%, 5>J !+@e been i"enti?ie". 1!ee 'ene +re m+inl2 +o$i+te" 4it! t!e
2n+pe ?un$tion (e.'., t+$!20inin, 2nu$lein, neuropepti"e Y, $o$+ine, +mp!et+mine7
reponi@e tr+n$ript, +n" 2n+ptoom+l7+o$i+te" protein 25 0#+); $+l$ium ion
re'ul+tion (e.'., p+r@+lbumin, @iinin7li0e, +n" $+"!erin); immune +n" in?l+mm+tor2
repone (m+Mor !ito$omp+tibilit2 $ompleL (MH() $l+ ))), +n" +poptoi ($!oliner'i$
re$eptor).
Anot!er tu"2 I65J in@eti'+te" t!e e??e$t o? prion p+t!o'enei on 'ene eLpreion in
$+ttle uin' mi$ro+rr+2 +n" 11> 'ene rel+te" to immune repone, +poptoi, $ell
+"!eion, tre repone, +n" tr+n$ription 4ere ?oun" to be "i??erenti+ll2 re'ul+te"
(1+ble ; ;). #ue to in!erent limit+tion o? mi$ro+rr+2 in$lu"in' eDuen$e7pe$i?i$ probe
!2bri"i<+tion, b+$0'roun" +n" $ro7!2bri"i<+tion o? rel+te" 'ene, "i'it+l 'ene
eLpreion (#G:) t+' pro?ilin' uin' neLt 'ener+tion eDuen$in' 4+ ue" to $omp+re
t!e tr+n$riptomi$ pro?ile o? me"ull+ tiue ?rom $+ttle in?e$te" 4it! /*: I55J. 1!i
tu"2 i"enti?ie" 190 #: tr+n$ript ?rom "i??erent p+t!4+2 in$lu"in' neuro+$ti@e
li'+n"re$eptor inter+$tion, re'ul+tion o? t!e +$tin $2to0eleton, ?o$+l +"!eion, *5A8:
inter+$tion in @ei$ul+r tr+nport, 17$ell re$eptor i'n+lin', $+l$ium i'n+lin', 1GP7bet+
i'n+lin', +n" MAP6 i'n+lin'. )n+""ition, t!e 1+' pro?ilin' 4+ u$$e?ul in
i"enti?2in' +""ition+l p+t!4+2 li0e :rb/ i'n+lin', t!e 1 $ell re$eptor, t!e ;nt
i'n+lin', +nti'en pro$ein', $2to0ine7$2to0ine re$eptor inter+$tion, G+p Mun$tion, +n"
t!e PPA8 i'n+lin' + $omp+re" to t!e pre@iou mi$ro+rr+2 tu"ie on /*:7in?e$te"
me"ull+ tiue I5%, 55J. 1!e $ommon #: 'ene "ete$te" in +ll t!ee tu"ie I52755, 65J
on $+ttle 4ere: *100 $+l$ium bin"in' +n" (+lmo"ulin; Prol+$tin7rel+te" protein; G1P+e,
)MAP ?+mil2 member, Hito$omp+tibilit2 $ompleL, $l+ )), Met+llopepti"+e +n"
M2oin, Glut+t!ione * tr+n?er+e A, Al"o76eto re"u$t+e ?+mil2 +n" 5u$le+r re$eptor
ub?+mil2 'roup H.
1+ble %.
Hi'! 1!rou'!put Gene :Lpreion *tu"ie in Prion7in?e$te" #i??erent 1iue ?rom t!e
8umin+nt 3e+"in' to t!e )"enti?i$+tion o? M+Mor Pun$tion+l (+n"i"+te Gene & M+r0er &
P+t!4+2
.p7re'ul+tion o? t!ree $!+perone in$lu"in' en"opl+mi$ reti$ulum (:8) $!+perone,
Grp9> +n" Grp170 !+ tron'l2 u''ete" t!e preen$e o? :8 tre +n" t!e +$ti@+tion o?
t!e un?ol"e" protein repone (.P8) in /*:7in?e$te" $+ttle I66J. 1!e p+ttern o? 'ene
eLpreion in 4!ite bloo" $ell ?ollo4in' or+l in?e$tion o? $+ttle 4it! /o@ine +m2loi"oti$
pon'i?orm en$ep!+lop+t!2 (/A*:) !+ +lo been in@eti'+te" +n" i'ni?i$+nt $!+n'e in
eLpreion o? 'ene lin0e" to 17 +n" /7$ell "e@elopment +n" +$ti@+tion, +n" to
in?l+mm+tor2 repone 4+ ober@e" I67J. Hi'!7"enit2 4!ole 'enome +o$i+tion
tu"2 in 1>% /*: $+e +n" 17% $ontrol +nim+l elu$i"+te" $!romoom+l re'ion +n"
poition+l $+n"i"+te 'ene +o$i+te" 4it! "ie+e I28J. 1!ee poition+l $+n"i"+te 'ene
in$lu"e !2pot!eti$+l 'ene 3E(521010, imil+r to P6506 bin"in' protein 2 en$o"in' +
protein ?rom immunop!ilin protein ?+mil2 4it! + role in protein ?ol"in', leu$ine7ri$!
repe+t +n" immuno'lobulin7li0e "om+in 2, 38)G2, + protein 0no4n to be in@ol@e" in
protein7protein inter+$tion, +n" 8epuli@e 'ui"+n$e mole$ule ?+mil2 member A, +
'l2$o2l p!op!+ti"2linoitol 7+n$!ore" 'l2$oprotein, 4it! + role + +n +Lon 'ui"+n$e
protein in t!e $entr+l ner@ou 2tem I28J.
8e$entl2, tr+n$riptomi$ +n+l2i in t!e $+u"+l me"ull+ oblon'+t+ o? $r+pie7
2mptom+ti$ !eep uin' + (=) $utom "ei'ne" >L>>6 mi$ro+rr+2 pl+t?orm i"enti?ie"
1>8 'ene (1+ble ; ;) t!+t +re prim+ril2 +o$i+te" 4it! t!e immune repone, ion
tr+nport, $ell +"!eion, +n" tr+n$ription I68J. 1r+n$riptome +n+l2i o? $r+pie7in?e$te"
l2mp! no"e +n" pleen tiue ?rom !eep !+@e re@e+le" t!e repreion o? 'ene lin0e"
to in?l+mm+tion +n" oLi"+ti@e tre, +n" t!e up7re'ul+tion o? 'ene rel+te" to +poptoi
I69J. ;e per?orme" ?irt $ompre!eni@e mi$ro+rr+2 +n+l2i o? !i'!7t!rou'!put 'ene
eLpreion +o$i+te" 4it! (;# "ie+e uin' bo@ine pe$i?i$ oli'o. 1!e "i??erenti+l
eLpreion o? + et o? 0e2 'ene ?rom "i??erent p+t!4+2 ?rom multiple or'+n o? (;#
in?e$te" el0 in$lu"e m+Mor re'ul+tor2 +n" i'n+lin' net4or0, neuron+l i'n+lin', 2n+pe
?un$tion in neurolo'i$+l "ie+e, $+l$ium i'n+lin', +poptoi +n" $ell "e+t!, +n" immune
$ell tr+??i$0in' +n" in?l+mm+tor2 repone I70J.
)n t!i re@ie4, 4e !+@e umm+ri<e" t!e emer'in' role o? ?un$tion+l 'enomi$
te$!nolo'ie in i"enti?2in' 'eneti$ $!+n'e 4!i$! $oul" be ue" + potenti+ll2 "i+'noti$
biom+r0er ?or ri0 "etermin+tion +n" + 'ener+l in"i$+tor o? "ie+e pro'reion. Mot
o? t!e eLpreion pro?ilin' tu"ie per?orme" o ?+r +re in "i??erent mo"el +?ter $lini$+l
2mptom +ppe+r, !o4e@er, prion "ie+e +n" ot!er neuro"e'ener+ti@e "ior"er !+@e +
lon' pre72mptomi$ p!+e I71J. A""ition+l tu"ie 4ill be ne$e+r2 to in@eti'+te
"i??erenti+l 'ene eLpreion t!rou'! ?ull tr+n$riptomi$ +n+l2i ?rom +nim+l +t bot! pre7
$lini$+l +n" $lini$+l time point to i"enti?2 ne4 'ene, protein +n" p+t!4+2 in@ol@e" in
t!e p+t!o'enei o? 1*: in or"er to ele$t 'ene() 4!i$! $oul" be ue" + + pre7$lini$+l
"i+'noti$ m+r0er.
Go to:
G)PI!N "I&%A&%& AN" !T+%
N%#!"%G%N%ATI,% "I&!"%&
Mi7?ol"in' o? t!e prion protein +n" it pro'rei@e +$$umul+tion into +''re'+te i t!e
$ommon ?e+ture o? m+n2 m+Mor neuro"e'ener+ti@e "ie+e, li0e A#, P+r0inonN "ie+e
(P#), ?ronto7tempor+l "ementi+, Huntin'tonN "ie+e (H#) 4!i$! i !+re" b2 1*: or
prion "ior"er li0e (-# I72, 7%J. )n +ll t!ee neurolo'i$+l "ie+e, t!ere i $ontinue"
2nt!ei o? mut+nt, +''re'+tion7prone protein u$! + t+u (in 1+up+t!ie), w72nu$lein
(in P#), pol2'lut+mine7$ont+inin' protein (in H#), +n" +m2loi"7m (in A#) ?or m+n2
"e$+"e be?ore neurop+t!olo'2 2mptom +re e@i"ent I1%J. Purt!ermore, t!ee protein
or protein +''re'+te in"i$+te Wprion7li0eX p!enomenon o? (-# +n" /*: +n" !+@e been
!o4n to pre+" to ot!er $ell +n" br+in re'ion reultin' in t!e pro'rei@e "eterior+tion
I7>, 75J. Prion "ie+e +n" A# !+re ome $ommon morp!olo'i$+l +n"
p+t!op!2iolo'i$+l ?e+ture in$lu"in' t!e $opper bin"in' propertie o? t!e +m2loi"o'eni$
protein, oLi"+ti@e tre +n" t!e e@i"en$e o? ?ree r+"i$+l "+m+'e, t!e ?orm+tion o?
+m2loi" pl+Due +n" neuro?ibrill+r2 p+t!olo'2 I1%, 76J. Hitolo'i$+l +n" bio$!emi$+l
tu"ie I77, 78J !+@e re$entl2 u''ete" t!+t Al<!eimerX "ie+e +n" 1*: p+t!olo'ie
2ner'iti$+ll2 inter+$t 4it! t!e poibilit2 o? + "ire$t inter+$tion bet4een t!e protein
le+"in' to $ro7ee"in' +n" in$re+e" p+t!o'enei 4it! t!e poibilit2 o? mole$ul+r
$ro t+l0 bet4een bot! "ie+e. 1!i inter+$tion m+2 "irupt inter+$tion bet4een PrP
$

+n" + $o7re$eptor imp+irin' t!e neuronX i'n+l7tr+n"u$tion p+t!4+2 le+"in' to +m2loi"
m oli'omeri<+tion outi"e t!e $ell +n" intr+$ellul+r +$$umul+tion o? t+u protein le+"in' to
2n+pti$ pl+ti$it2, +Lon+l "+m+'e +n" neuron+l "e+t! I77779J.
)n +""ition to t!e $ommon !itop+t!olo'i$+l ?e+ture, oLi"+ti@e tre Pi'. (1 1) i +n
import+nt ?+$tor t!+t !+ been impli$+te" in t!e p+t!o'enei o? + number o?
neuro"e'ener+ti@e "ior"er I58J. 1!e mi?ol"in' o? protein or t!e "e@elopment o?
pl+Due i ?ollo4e" b2 lo o? 2n+pe +n" poible +bnorm+litie in mito$!on"ri+l
?un$tion. )n$re+e" eniti@it2 to oLi"+ti@e tre in neuro"e'ener+ti@e "ie+e i t!rou'!
+lter+tion o? +nti7oLi"+nt en<2me ?un$tion, +n" in$re+e" lipi" peroLi"+tion reultin' in
imp+irment o? +nti7oLi"+nt repone I80J. 1!ere i in$re+in' e@i"en$e t!+t e$on"+r2
mito$!on"ri+l "2?un$tion b2 in!ibition o? e@er+l 0e2 en<2me in t!e mito$!on"ri+l
ener'2 pro"u$tion p+t!4+2 or t!rou'! t!e tri''erin' o? $+p+e7"epen"ent +poptoi
o$$ur in + number o? m+Mor neuro"e'ener+ti@e "ie+e I81J. )n +""ition, oLi"+ti@e tre
+n" +poptoi in prion "ie+e reult in en"opl+mi$ reti$ulum tre t!rou'! t!e
"iruption o? $+l$ium !omeot+i in t!e $ell $+uin' $+l$ium o@erlo+" in t!e $2topl+m
le+"in' to 2n+pti$ lo +n" neuron+l "e+t! I82J. Et!er tu"ie !+@e +lo re@e+le" t!+t t!e
o@er+ll le@el o? oLi"+ti@e "+m+'e to protein, lipi" +n" #5A m+2 reult in ubiDuitin7
prote+ome "2?un$tion le+"in' to neuron+l "e'ener+tion I8%J. *in$e t!e mole$ul+r
p+t!4+2 in@ol@e" in "i??erent neuro"e'ener+ti@e "ie+e +re imil+r, ?urt!er tu"ie to
eLplore t!ee mole$ul+r inter+$tion, uin' !i'! t!rou'!put ?un$tion+l 'enomi$
te$!nolo'ie $ombine" 4it! ne4 bioin?orm+ti$ $+p+bilitie, 4ill pro@i"e + ne4
$on$eptu+l ?r+me4or0 ?or t!e p+t!o'enei o? "i??erent neuro"e'ener+ti@e "ie+e +n"
4ill !+@e import+nt t!er+peuti$ impli$+tion.
Pi'. (1)
)n@ol@ement o? oLi"+ti@e tre in prion "ie+e +n" ot!er neuro"e'ener+ti@e "ie+e
le+"in' to mito$!on"ri+l "2?untion, en"opl+mi$ reti$ulum tre t!rou'! +ltere" 'ene
?un$tion.
Go to:
B)3#T#% "I%$TI!N&
.ntil no4, mot o? t!e ?un$tion+l 'enomi$ tu"ie !+@e emplo2e" mi$ro+rr+2 +n"
'enome 4i"e +o$i+tion tu"ie to i"enti?2 potenti+l $+n"i"+te 'ene or p+t!4+2
in@ol@e" in prion "ie+e in "i??erent mo"el or or'+nim. ;it! t!e re$ent +"@+n$e in
neLt 'ener+tion eDuen$in', eLome eDuen$in', l+r'e $+le "+t+ inte'r+tion +n" "+t+
minin', it !oul" be poible to in@eti'+te ot!er 0e2 re'ul+tor in$lu"in' mi85A, +n"
tr+n$ription ?+$tor pl+2in' + role in t!e p+t!o'enei me$!+nim I8>J. *ome
prelimin+r2 tu"ie +re be'innin' to et+bli! t!e role o? mi85A in prion "ie+e. 1!e
?irt $ompre!eni@e mi$ro+rr+2 +n+l2i o? mi85A eLpreion in t!e br+in o? mi$e
in?e$te" 4it! moue7+"+pte" $r+pie reporte" t!e "e7re'ul+tion o? 15 mi85A
$ontrollin' + number o? 'ene +n" i'n+lin' p+t!4+2 "urin' prion in"u$e"
neuro"e'ener+tion I85J. Anot!er tu"2 pro@i"e" e@i"en$e o? up7re'ul+tion o? mi85A7
1>6+ in por+"i$ (reut<?el"t7-+0ob "ie+e ((-#) +n" Gertm+nn7*tr+uler7*$!ein0er
2n"rome (G**) u''etin' it role in inn+te immune repone +n" +nti@ir+l immunit2
I86J. Port!$omin' "ire$tion o? ree+r$! 4ill ?o$u on + $o7or"in+te" +ppro+$! to lin0
tr+n$riptome +n" mi$ro85Aome "+t+ 4it! eLteni@e $omput+tion+l +n+l2i, neLt
'ener+tion eDuen$in' tu"ie p+nnin' t!e entire 'enome or eLome, +n+l2i o?
tru$tur+l 'eneti$ @+ri+tion ($op2 number @+ri+tion t!rou'! "eletion, "upli$+tion, +n"
in@erion) +n" 'enome 4i"e +o$i+tion +n+l2i. All t!ee tu"ie Pi'. (6 6) 4ill pro@i"e
ne4 ini'!t o? t!e re'ul+tor2 net4or0 in@ol@e" in prion p+t!o'enei o? !um+n +n"
+nim+l prion "ie+e. Prion +re +lo emer'in' + WeLtreme $+e o? epi'eneti$
in!erit+n$eX +n" prion b+e" me$!+nim m+2 in?luen$e 'eneti$ in?orm+tion I87J.
.n"ert+n"in' o? t!e epi'eneti$ in?orm+tion in +""ition to t!e 'eneti$ in?orm+tion i
be$omin' import+nt ?or t!e pre@enti@e "i+'noi +n" tre+tment o? "ie+e I88J. 1!e
+@+il+bilit2 o? neLt 'ener+tion eDuen$in' te$!nolo'ie 4ill empo4er t!e tu"2 o?
epi'eneti$ @+ri+tion in$lu"in' #5A met!2l+tion, !itone mo"i?i$+tion, +n" $!rom+tin
+$$eibilit2 4!i$! m+2 be in@ol@e" in prion +o$i+te" neuro"e'ener+ti@e "ior"er.
Purt!ermore, tu"ie uin' ?un$tion+l proteomi$ +n" ne4 p!2iolo'2 te$!niDue u$! +
l+er $+pture mi$ro"ie$tion on ubpopul+tion o? $ell in pre7 +n" pot72mptomi$
p!+e o? prion +n" ot!er neuro"e'ener+ti@e "ie+e 4ill $omplement t!e 'enomi$
tu"ie to "etermine ele$ti@e biom+r0er.
Pi'. (2)
.n"ert+n"in' o? $ompleL prion "ie+e: )"enti?i$+tion o? 'ene +n" 'eneti$ m+r0er
t!rou'! ?un$tion+l 'enomi$.
Go to:
A$/N!5'%"G%*%NT
#e$l+re" none.
Go to:
$!N3'I$T !3 INT%%&T
1!e +ut!or() $on?irm t!+t t!i +rti$le $ontent !+ no $on?li$t o? interet.
Go to:
%3%%N$%&
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%. )mr+n M, M+!moo" *. An o@er@ie4 o? +nim+l prion "ie+e. =irolo'2 -. 2011;8:>9%
>. Hu<+re4i$! 83, *iemen AG, /oot! *A. Appli$+tion o? Womi$X to prion biom+r0er
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5. A'u<2%:127129. IPubMe"J
6. ;ilemit! -;, 82+n -/, At0inon M-. /o@ine pon'i?orm en$ep!+lop+t!2:
epi"emiolo'i$+l tu"ie on t!e ori'in. =et. 8e. 1991;128:9920%. IPubMe"J
7. 5+t!+non 5, ;ilemit! -, Griot (. /o@ine pon'i?orm en$ep!+lop+t!2 (/*:): $+ue
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Pletteri$0 8-, (o!en P:. (on@erion o? w7!eli$e into m7!eet ?e+ture in t!e ?orm+tion
o? t!e $r+pie prion protein. Pro$. 5+tl. A$+". *$i. 199%;90:1096210966. IPM( ?ree
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10. /ilM+n ), )l$ G, Gi+$!in G, 8+p+"ori A, A!u0o@ ), Pl+@e$ -, 3e'n+me G. 1o4+r" t!e
Mole$ul+r /+i o? )n!erite" Prion #ie+e: 5M8 *tru$ture o? t!e Hum+n Prion Protein
4it! =210) Mut+tion. -. Mol. /iol. 2011;>12:66067%. IPubMe"J
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1%. Pr+er H, #i$0inon AG. *tu"ie o? t!e l2mp!oreti$ul+r 2tem in t!e p+t!o'enei o?
$r+pie: t!e role o? pleen +n" t!2mu. -. (omp. P+t!ol. 1978;88:56%57%. IPubMe"J
1>. 6imberlin 8H, ;+l0er (A. P+t!o'enei o? moue $r+pie: "2n+mi$ o? +'ent
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P+t!ol. 1979;89:551562. IPubMe"J
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$!romoom+l 'ene. (ell. 1986;>6:>17>28. IPubMe"J
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2n"rome. 5+ture. 1989;%%8:%>2%>5. IPubMe"J
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22. 8on'2+n A, î+n'lon' 3, 3+n!ui 3, î+n'2un 3, PuMun P. :@olution +n"
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2%. (olb2 #;, Pruiner */. Prion. (ol" *prin' H+rb. Perpe$t. /iol. 2011;%:+0068%%.
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Genome. 2002;1%:16>168. IPubMe"J
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%1. Moreno (8, 3+ntier P, 3+ntier ), *+rr+"in P, :len -M. #ete$tion o? ne4 Du+ntit+ti@e
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6>. 1orto+ 8, (+tell ^, =i"+l :, (ot+ (, 8ui< "e =ill+ M"el (, *an$!e< A, /+r$eli A,
1orre -M, Pum+rol+ M, Arixo -. (entr+l ner@ou 2tem 'ene eLpreion $!+n'e in +
tr+n'eni$ moue mo"el ?or bo@ine pon'i?orm en$ep!+lop+t!2. =et. 8e. 2011;>2:109
12%. IPM( ?ree +rti$leJ IPubMe"J
65. 1+n' Y, î+n' ;, H+40in *A(, 6ret<$!m+r HA, ;in"t E. 1r+n$ription+l $!+n'e
in t!e br+in o? $+ttle or+ll2 in?e$te" 4it! t!e bo@ine pon'i?orm en$ep!+lop+t!2 +'ent
pre$e"e "ete$tion o? in?e$ti@it2. -. =irol. 2009;8%:9>6>9>7%. IPM( ?ree +rti$leJ
IPubMe"J
66. 1+n' Y, î+n' ;, 1err2 3, 6ret<$!m+r HA, ;in"l E. 1r+n$ription+l +n+l2i
impli$+te en"opl+mi$ reti$ulum tre in /o@ine *pon'i?orm :n$ep!+lop+t!2. P3o*
E5:. 2010;5 e1>207. "oi:10.1%71&Mourn+l.pone.001>207. IPM( ?ree +rti$leJ IPubMe"J
67. P+nelli *, *tro<<i P, (+po?erri 8, /+rbieri ), +rtinelli 5, (+pu$$i 3, 3omb+r"i G,
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4it! /o@ine +m2loi"oti$ pon'i?orm en$ep!+lop+t!2. -. 1oLi$ol. :n@iron. He+lt!, P+rt A.
2011;7>:96102. IPubMe"J
68. Pil+li H, M+rtin7/urriel ), H+r"er P, =+ron+ 3, 32+!2+i -, A+r+'o<+ P, Pum+rol+ M,
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rel+te" leion in t!e me"ull+ oblon'+t+ o? 2mptom+ti$ n+tur+l $r+pie +nim+l. P3o*
E5:. 2011;6 e19909. "oi: 10.1%71&Mourn+l.pone.0019909. IPM( ?ree +rti$leJ IPubMe"J
69. Goner A, 8oup+0+ *, Poter -, Hunter 5, Hop0in -. 1r+n$ription+l pro?ilin' o?
perip!er+l l2mp!oi" tiue re@e+l 'ene +n" net4or0 lin0e" to **/P&1 $r+pie
p+t!olo'2 in !eep. =et. Mi$robiol. 2011;15%:218228. IPubMe"J
70. /+u ., Almei"+ 3M, #u"+ *, Gr+!+m (:, (<ub *, Moore **, Gu+n 33. Gene
eLpreion +lter+tion in ro$02 mount+in el0 in?e$te" 4it! $!roni$ 4+tin' "ie+e. Prion.
71. /enetti P, Gutin$i$! *, 3e'n+me G. Gene eLpreion pro?ilin' +n" t!er+peuti$
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72. (!iti P, #obon (M. Protein mi?ol"in', ?un$tion+l +m2loi" +n" !um+n "ie+e.
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7%. -ellin'er 6A. )nter+$tion bet4een p+t!o'eni$ protein in neuro"e'ener+ti@e "ior"er.
-. (ell Mol. Me". 2011. #E): 10.1111&M.15827>9%>.2011.01507.L. IPubMe"J
7>. Prot /, #i+mon" M). Prion7li0e me$!+nim in neuro"e'ener+ti@e "ie+e. 5+ture
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75. Guet ;(, *il@erm+n M, Po0ri!e@02 :, EX5eil MA, Gr+" 3), (+!m+n 58.
Gener+liL+tion o? t!e prion !2pot!ei to ot!er neuro"e'ener+ti@e "ie+e: An imper?e$t
?it. -. 1oLi$ol. :n@iron. He+lt!, P+rt A. 2011;7>:1>%%1>59. IPubMe"J
76. (+tell+ni 8-, Perr2 G, *mit! MA. Prion "ie+e +n" Al<!eimerX "ie+e,
p+t!o'eni$ o@erl+p. A$t+. 5eurobiol. :Lp. 200>;6>:1117. IPubMe"J
77. (ie M, Mu$0e 3. A prion protein $onne$tion. 5+ture. 2009;257:10901091.
IPubMe"J
78. Mor+le 8, :tr+"+ 3#, #i+<7:pinoL+ 8, Mor+le7*$!ei!in' #, -+r+ M(, (+till+ -,
*oto (. Mole$ul+r $ro t+l0 bet4een mi?ol"e" protein in +nim+l mo"el o? Al<!eimerX
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79. *oto (. 1r+nmiible protein: :Lp+n"in' t!e prion !ere2. (ell. 2012;1>9:968977.
80. Mil!+@et E, 3e!+mnn *. ELi"+ti@e tre +n" t!e prion protein in tr+nmiible
pon'i?orm en$ep!+lop+t!i. /r+in 8ee+r$! 8e@ie4. 2002;%8:%28%%9. IPubMe"J
81. M+n$uo M, *i$ili+no G, Piloto M, Murri 3. Mito$!on"ri+l "2?un$tion +n"
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82. *oto (, *+t+ni 5. 1!e intri$+te me$!+nim o? neuro"e'enr+tion in prion "ie+e.
1ren" Mol Me"i$ine. 2011;17:1>2>. IPM( ?ree +rti$leJ IPubMe"J
8%. Gi+on /), 3ee =M7Y, 1roM+no40i -O. 1!e rel+tion!ip bet4een oLi"+ti@e&nitr+ti@e
tre +n" p+t!olo'i$+l in$luion in Al<!eimerN +n" P+r0inonN "ie+e. Pree 8+"i$+l
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8>. Pro@ot P. Mi$ro85A + + mole$ul+r b+i ?or ment+l ret+r"+tion, Al<!eimerN +n"
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85. *+b+ 8, Goo"m+n (#, Hu<+re4i$! 83, 8oberton (, /oot! *A. A mi85A i'n+ture
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86. 3u0i4 ;-, #u+ P, Po'ue A), :i$0en (, Hill -M. .pre'ul+tion o? mi$ro 85A71>6+
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-+0ob "ie+e ((-#) +n" Gertm+nn7*tr+uler7*$!ein0er (G**) 2n"rome. -. 1oLi$ol.
:n@iron. He+lt! A. 2011;7>:1>601>68. IPM( ?ree +rti$leJ IPubMe"J
87. H+l?m+nn 8, 3in"Duit *. :pi'eneti$ in t!e eLtreme: prion +n" t!e in!erit+n$e o?
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Jurnal F
Virulence. 2013 July 1; 4(5): 373383.
Publise! "nline 2013 #$ril 30. !"i: 10.4161%&iru.24838
PMCID: P'(3714129
Infectious particles: stress: and induced
prion amyloids
# uni)yin* $ers$ec+i&e
,-ur- '-nueli!is
#u+"r in)"r.-+i"n / #r+icle n"+es / ("$yri*+ -n! ,icense in)"r.-+i"n /
0" +":
Abstract
1r-ns.issible ence$-l"$-+ies (123s) -re belie&e! by .-ny +" -rise by
s$"n+-ne"us c"n&ersi"n ") "s+ $ri"n $r"+ein (PrP) in+" -n in)ec+i"us -.yl"i!
(PrP4res5 PrP
2c
) 6i+"u+ nucleic -ci!. '-ny 123 -*en+s resi!e in +e
en&ir"n.en+5 6i+ in)ec+i"n c"n+r"lle! by $ublic e-l+ .e-sures. 1ese
inclu!e +e !is-$$e-r-nce ") 7uru 6i+ +e cess-+i"n ") ri+u-l c-nnib-lis.5
+e !r-.-+ic re!uc+i"n ") e$i!e.ic b"&ine ence$-l"$-+y (823) by re."&-l
") c"n+-.in-+e! )ee!5 -n! +e l-c7 ") en!e.ic scr-$ie in *e"*r-$ic-lly
is"l-+e! #us+r-li-n see$ 6i+ susce$+ible PrP *en"+y$es. 9ile $ri"n $r"+ein
."!elin* -s en*en!ere! -n in+ense )"cus "n c".."n +y$es ") $r"+ein
.is)"l!in* -n! -.yl"i! )"r.-+i"n in !i&erse "r*-nis.s -n! !ise-ses5 +e
bi"l"*ic-l c-r-c+eris+ics ") in)ec+i"us 123 -*en+s5 -n! +eir rec"*ni+i"n by
+e "s+ -s )"rei*n en+i+ies5 r-ises se&er-l )un!-.en+-l ne6 !irec+i"ns )"r
)rui+)ul in&es+i*-+i"n suc -s: (1) unrec"*ni:e! .icr"bi-l -*en+s in +e
en&ir"n.en+-l .e+-*en".e +-+ .-y c-use l-+en+ neur"!e*ener-+i&e
!ise-se5 (2) +e e&"lu+i"n-ry s"ci-l -n! $r"+ec+i&e )unc+i"ns ") !i;eren+
-.yl"i! $r"+eins in !i&erse "r*-nis.s )r". b-c+eri- +" .-..-ls5 -n! (3)
-.yl"i! )"r.-+i"n -s - bene<ci-l inn-+e i..une res$"nse +" s+ress
(in)ec+i"us -n! n"n4in)ec+i"us). 1is inn-+e $r"cess "6e&er5 "nce ini+i-+e!5
c-n bec".e uns+"$$-ble in -cceler-+e! neur"n-l -*in*.
Keywords: +r-ns.issible ence$-l"$-+ies5 en&ir"n.en+-l $-+"*ens5
l-+ency5 ye-s+ $ri"ns5 bi"<l.s5 .e+-*en".e5 -*in*5 #l:ei.er !ise-se5
P-r7ins"n !ise-se5 nucleic -ci!s
=) = +"l! i.. 9"ul! e li7e i+ 6"ul! >-$"le"n?0er+ru!e 2+ein
0" +":
Introduction
1e $ur$"se ") +is $ers$ec+i&e is +" c"..unic-+e se&er-l )un!-.en+-l
bi"l"*ic )e-+ures ") 123 in)ec+i"ns +-+ .-y n"+ be -$$-ren+ +" scien+is+s 6"
!" n"+ is"l-+e -n! c-r-c+eri:e in)ec+i"us $-r+icles5 "r -n-ly:e !i;eren+ 123
-*en+4s+r-ins. #+ i* .ul+i$lici+y5 123 -*en+s c-n in!uce $-+"l"*ic-l
.is)"l!in* ") "s+ PrP in+" PrP4res -.yl"i!. @"6e&er5 in)ec+i"n is n"+ reAuire!
)"r +is c"n&ersi"n5 -n! *ene+ic "s+ PrP c"!in* .u+-+i"ns -re suBcien+ +"
c-use PrP -.yl"i! $l-Aues 6i+ n" in)ec+i&i+y.
144
CPri"nD -.yl"i! s+-+es in
ye-s+ -n! b-c+eri- +-+ l-c7 +e in)ec+i"us c-r-c+eris+ics ") .-..-li-n 123s
illus+r-+e -.yl"i! c".."n-li+ies5 -s 6ell -s +e )unc+i"n-l !i&ersi+y ") $r"+ein
-**re*-+i"n in e&"lu+i"n. Eni+y in +e C$ri"nD <el! rel-+es -.yl"i! $r"cesses5
bu+ n"+ +e !i&erse inci+in* c-uses ") $r"+ein -**re*-+i"n. #u+"c-+-ly+ic PrP4
res -ccu.ul-+i"n )"ll"6s - .-r7e!ly !i;eren+ +r-Fec+"ry +-n +e re$lic-+i"n
") in)ec+i"us 123 $-r+icles5 -s !e+-ile! bel"6. 8ec-use PrP b-n! $-++erns
nei+er c"rrel-+e 6i+ n"r $re!ic+ -*en+ s+r-in $r"$er+ies +-+ -re $reser&e!
-cr"ss s$ecies5 n"n4PrP ."lecules .us+ !e+er.ine s+r-in c-r-c+eris+ics.
'-..-ls in+er-c+ 6i+ +rilli"ns ") .icr""r*-nis.s "n +e s7in -n! in +e
-li.en+-ry +r-c+5 $"sin* .-ny "$$"r+uni+ies )"r eGc-n*e -n!%"r
inc"r$"r-+i"n ") )"rei*n nucleic -ci!. 123 in)ec+i"us -*en+s c-n re$resen+ +e
+i$ ") +e iceber* ") i!!en en&ir"n.en+-l $-+"*ens +-+ c-use l-+e "nse+
!ise-se.
H"r si.$lici+y5 c".$"si+e 123 !-+- -re <rs+ br"-!ly su..-ri:e!5 6i+
illus+r-+i"ns ") 6ell4es+-blise! )-c+s. 123s5 by !e<ni+i"n5 -re - *r"u$ ")
rel-+e! .-..-li-n in)ec+i"ns +-+ -re le+-l "nce +ey in&-!e +e br-in.
#c+i&e br-in in)ec+i"n se$-r-+es 123s )r". "+er neur"!e*ener-+i&e !ise-ses5
suc -s #l:ei.er !ise-se (#I) -n! $"s+4ence$-li+ic ($"s+4in)ec+i"us)
P-r7ins"n !ise-se5 +-+ s-re $r"+ein .is)"l!in* .ec-nis.s -n! -.yl"i!
$en"+y$es bu+ -re n"+ in)ec+i"us. #.yl"i! $l-Aues -&e l"n* been 7n"6n +"
)"r. in +e br-ins ") n"r.-l "l!er -ni.-ls5 $-r+icul-rly $ri.-+es5 -n!
in"cul-+i"n ") #I J4-.yl"i! "."*en-+es in +e br-in "nly -cceler-+es -*in*5
bu+ !"es n"+ +r-ns.i+ - re$lic-+in* in)ec+i"us -*en+.
5
1e r-re *ene+ic c-ses
") u.-n #I -n! $ri"n $-+"l"*y5 -l"n* 6i+ +r-ns*ene (1*) ."!els )"r #I
J4-.yl"i! -n! PrP -.yl"i! !e$"si+i"n5 un!ersc"re n"n4in)ec+i"us c-uses ")
+e s-.e en!4s+-*e $en"+y$e "r -.yl"i! sc-r. (u.ul-+i&e en&ir"n.en+-l
)-c+"rs5 inclu!in* +"Gins -n! $-s+ in)ec+i"ns +-+ c-n li.i+ +e li)es$-n ") n"n4
!i&i!in* neur"ns5 -re li7ely +" c-use +e ."re c".."n )"r.s n"n4in)ec+i"us
#I.
6
=n c"n+r-s+5 - )"rei*n in)ec+i"us -*en+ is +e r""+ c-use ") 123s5 - )-c+
+-+ -s been "bscure! by +e -ssu.$+i"n +-+ "s+4enc"!e! PrP4res is +e
in)ec+i"us -*en+. Kr5 -s ."re $r"ibi+i&ely s+-+e!: CPri"ns -re c".$"se!
s"lely ") +e !ise-se4c-usin* $ri"n $r"+ein (PrP
2c
)D.
7
1is eGclusi&e &ie6
c"n+inues +" be $r".ul*-+e!
859
e&en +"u* "+er ."lecules5 inclu!in*
nucleic -ci!s5 c-n be reAuire! )"r re$lic-+i"n ") 123 in)ec+i"us -*en+s.
10
1e s+ruc+ure -n! in+e*r-l ."lecules ") +e in)ec+i"us 123 $-r+icle re.-in
un!e<ne!. 1" !-+e5 PrP4res i+sel) -s )-ile! +" )ul<lle! L"c $"s+ul-+es.
11512

L"c $"s+ul-+es re.-in $-r+icul-rly rele&-n+ n"6 bec-use rec".bin-n+ -n!
syn+e+ic nucleic -ci!s5 6i+"u+ +e nee! )"r cul+ure5 -re suBcien+ +" recre-+e
in)ec+i"n -n! i+s c-r-c+eris+ic !ise-se $en"+y$e5 -s s"6n )"r $"li"&irus.
2i.il-rly5 .-ny recen+ 123 in&es+i*-+i"ns -&e -++e.$+e! +" $r"&e +e $ri"n
y$"+esis by )"cusin* "n +es+ +ube -u+"c-+-ly+ic c"n&ersi"ns ") n"r.-l PrP
+" - .is)"l!e!5 $resu.-bly in)ec+i"us PrP4res. =n +ese eG$eri.en+s5
in)ec+i"us .-+eri-l is <rs+ use! +" s+-r+ "r Csee!D +e -.yl"i!"*enic $r"cess.
1ese -.yl"i! c"n&ersi"n re-c+i"ns5 seAuen+i-lly re$lenise! 6i+ unin)ec+e!
.-+eri-l5 suc -s n"r.-l br-in "."*en-+es5 +y$ic-lly *ener-+e en"r."us
-."un+s ") PrP4res 6i+ li++le5 "r n" in)ec+i&i+y. 1us +e .is)"l!e! PrP4res
$r"+ein -l"ne is n"+ necess-rily in)ec+i"us. PrP4res -s -ls" been *ener-+e!
)r". n"r.-l br-in. 1is s"6s +-+ PrP4res )"r.-+i"n -n! in)ec+i"us -*en+
re$lic-+i"n -re +6" !i;eren+ $r"cesses.
'-ny s+u!ies -c7n"6le!*e +-+ s".e "+er Cc")-c+"rD is reAuire! +" .-7e
PrP in)ec+i"us5
10513514
bu+ "nly "ne *r"u$ -s re$"r+e! +-+ rec".bin-n+ PrP
(recPrP) c-n be c"n&er+e! in+" -n in)ec+i"us )"r. 6i+"u+ -ny -ni.-l !eri&e!
-!!i+i&es "r Csee!sD.
15
1is resul+ -s ne&er been re$lic-+e! by "+ers "&er
+e $-s+ 8 y5 -n! seri-l +r-ns.issi"ns )r". +-+ recPrP in 6+ .ice re&e-le!
incub-+i"n +i.es -n! neur"$-+"l"*y ") +eir l-b"r-+"ry scr-$ie s+r-in (M',);
l-b"r-+"ry c"n+-.in-+i"n is -n -c7n"6le!*e! $r"ble. in +es+ +ube PrP4res
c"n&ersi"ns.
16
#n"+er *r"u$ -s -ls" cl-i.e! in +eir -bs+r-c+ +-+ in)ec+i&i+y
Cc-n be *ener-+e! s"lely )r".N recPrP 6i+"u+ -ny .-..-li-n "r syn+e+ic
c")-c+"rsD5 bu+ +e eG$eri.en+-l !e+-ils s"6 +-+ - s+-n!-r! scr-$ie br-in
PrP4res $re$-r-+i"n5 7n"6n +" c"n+-in in)ec+i&i+y (-s 6ell -s nucleic -ci!)5 6-s
-!!e! +" see! +is recPrP re-c+i"n.
17
=n - s+u!y +-+ .-y be ."re c"n&incin*5
+issue !eri&e! li$i!s 6ere -!!e! +" recPrP +" $r"!uce unusu-lly i* le&els ")
l-b4li7e scr-$ie in)ec+i&i+y.
18
Iurin* +e $-s+ 3 y +is resul+ -$$-ren+ly -s n"+
been re$r"!uce! else6ere by in!e$en!en+ in&es+i*-+"rs. 2ubseAuen+
c"n&ersi"n s+u!ies5 6i+ li$i! -n! syn+e+ic $"ly(r#) M># -ls" s"6e! "nly
&ery .-r*in-l in)ec+i&i+y in -ni.-ls5 -n! Aues+i"n-ble PrP4res $-+"l"*y5 in
c"n+r-s+ +" -!!e! +issue !eri&e! M>#.
19
1us -n -*en+ M># c-nn"+ be rule!
"u+ -s cl-i.e!. >"+6i+s+-n!in* +e !i-*n"s+ic $"+en+i-l ") +ese PrP
c"n&ersi"ns5
20
+e $ur$"se ") +is re&ie6 is +" c"&er subs+-n+i-l bi"l"*ic-l -n!
-n-ly+ic-l e&i!ence +-+ in&i+es - ."re inclusi&e -$$reci-+i"n ") -l+ern-+i&e
-*en+ c"nce$+s. =n $-r+icul-r5 +e en&ir"n.en+-l s"urce ") in)ec+i"n5 +e
&-rie+y -n! $ersis+ence ") !i;eren+ -*en+ s+r-ins5 +e s$ecies -n! cell
res$"nses +" +ese !is+inc+ -*en+ s+r-ins5 -n! +e $resence ") nucleic -ci!s in
i*ly in)ec+i"us $-r+icles -ll le-! +" c"nsi!er-+i"n ") - nucleic -ci! *en".e
+-+ !e<nes 123 s+r-in &irulence -n! .u+-bili+y.
21
0" +":
outes of Infection and &pecies "etermine Prolonged
'atency
'-ny !ec-!es ") 6"r7 -&e s"6n +-+ e&en in+r-cerebr-l (ic) in"cul-+i"ns ")
s$ecies4-!-$+e! 123 -*en+s yiel! &ery l"n* incub-+i"n +i.es +" !ise-se.
1ese +y$ic-lly r-n*e )r". 100 ! +" 500 ! in r"!en+s in)ec+e! 6i+ !i;eren+
(JI -n! scr-$ie s+r-ins.
22
1e incub-+i"n +i.e !e$en!s "n +e 123 -*en+Os
&irulence )"r +e s$ecies in"cul-+e!. @-.s+ers5 r-+s5 .ice5 *uine- $i*s -n!
$ri.-+es -&e !i;eren+ i..une re$er+"ires +-+ -;ec+ -*en+ s$re-! -n!
$-+"l"*y5 -s -s been s"6n by $-ss-*e ") s$"r-!ic (JI (s(JI) -*en+s in
+ese !i;eren+ s$ecies
23
(&i!e in)r-). Peri$er-l in)ec+i"ns by in+r-$eri+"ne-l5
in+r-&-scul-r -n! "r-l r"u+es (+e ."s+ n-+ur-l)5 c-n +-7e -n e&en l"n*er +i.e
+" $r"!uce !ise-se +-n +e ic r"u+e5 e&en 6i+ - &irulen+ 123 -*en+ +-+ is
C)-s+D )"r - *i&en s$ecies5 suc -s 263L scr-$ie +-+ ic 7ills -.s+ers in P65
!. Me*-r!less ") r"u+e5 -s l-+er !e+-ile!5 l-+ency is l-r*ely b-se! "n "s+
rec"*ni+i"n -n! su$$ressi"n ") - )"rei*n -*en+ +-+ !6ells in -n! !eri&es
)r". +e en&ir"n.en+.
Kr-l -!.inis+r-+i"n ") +e 263L scr-$ie -*en+ in -.s+ers c-n yiel!
$r"l"n*e! -sy.$+".-+ic incub-+i"n +i.es5 ye+ s+ill le-! +" le+-l !ise-se
e&en 6en -!.inis+ere! )r". "l! s"il s-.$les5 +e c".."n s"urce ")
c"n+inu"us en!e.ic scr-$ie in EL -n! =cel-n!ic see$.
24525
Kn +e "+er -n!5
re$e-+e! i* "r-l !"sin* ") .ice 6i+ +e &irulen+ #si-+ic HE4(JI -*en+ )-ils
+" $r"!uce !ise-se 6i+in +e n"r.-l ."use li)es$-n.
26
1us .ice c-n
su$$ress -n!%"r eli.in-+e +is -*en+ $eri$er-lly. =n u.-ns5 -sy.$+".-+ic
in)ec+i"ns c-n be -s l"n* -s 530 y )r". +e +i.e ") eG$"sure5 -s es+-blise!
in 7uru5
27
-)+er $eri$er-l in"cul-+i"ns ") s(JI c"n+-.in-+e! *r"6+ "r."ne5
-n! in +e e$i!e.ic s$re-! ") +e 823 -*en+ +" :"" -ni.-ls -n! u.-ns
(&(JI) &i- c"n+-.in-+e! )ee!. # curren+ unc"n+r"lle! 123 ") cer&i!s ((9I)
c"n+inues +" s$re-! *e"*r-$ic-lly -cr"ss +e Eni+e! 2+-+es +" 6il! !eer -n!
el7. 1e en&ir"n.en+-l s"urce ") in)ec+i"n is cle-r in -ll +ese .-F"r 123
in)ec+i"ns. Knly in s(JI5 - rel-+i&ely r-re -n! -&irulen+ 1235 is +e
en&ir"n.en+-l s"urce n"+ "b&i"us. @ence s(JI is - s$"r-!ic5 bu+ n"+
necess-rily Cs$"n+-ne"usD in)ec+i"n.
28
16" rel-+e! $r"ble.s )ur+er c"n)r"n+ -n Cin)ec+i"us PrP4resD. Hirs+5 "r-l
!"sin* eG$eri.en+s s"6 +-+ +e in)ec+i"us -*en+5 bu+ n"+ PrP4res5 sur&i&es
+e !i*es+i&e Fuices.
29530
#*en+5 bu+ n"+ PrP sur&i&-l is n"6 )ur+er
subs+-n+i-+e! by $r"+ein-se L (PL) !i*es+i"ns +-+ !es+r"y -ll )"r.s ") PrP5
inclu!in* +e rel-+i&ely PL resis+-n+ Cin)ec+i"usD PrP4res )"r..
31
'"re"&er5
i* le&els ") in)ec+i"us -*en+ -re Au-n+i+-+i&ely rec"&ere! )r". !i*es+e!
br-in5 e&en -)+er P3 l"*s ") PrP -n! PrP4res -re !es+r"ye!. 1is 6"ul!
l"*ic-lly le-! +" -n eG-.in-+i"n ") n"n4PrP -*en+ c".$"nen+s5 es$eci-lly
."lecules -n! &ir-l s+ruc+ures bes+ !esi*ne! +" in)ec+ .-..-ls &i- +e "r-l
r"u+e. 1ese inclu!e &iruses5 6i+ +eir $r"+ec+e! nucleic -ci!s5 +-+ -re $-r+
") +e &-s+ .e+-*en".e. ('e+-*en".e
32
re)ers +" $re&i"usly un7n"6n
c"..uni+ies ") .icr"bi-l "r*-nis.s in +e en&ir"n.en+ +-+ -re bein*
!isc"&ere! usin* *ene+ic seAuencin* r-+er +-n l-b"r-+"ry cul+i&-+i"n.) 1e
sec"n! c"nun!ru. r-ise! by $r"l"n*e! $eri$er-l l-+ency is "6 -ny )"r. ")
PrP5 "r - s$"n+-ne"us PrP4res see!5 c-n ."!ul-+e i+s "6n Auiescence in -
+issue s$eci<c 6-y5 -n! +en su!!enly rele-se i+sel) +" unce-sin*ly re$lic-+e
6i+ - s+r-in4s$eci<c !"ublin* +i.e in br-in.
33
@"s+ c"n+r"ls ") - )"rei*n
en&ir"n.en+-l -*en+ 6"ul! +y$ic-lly be in&"l&e! in +is +y$e ") $-++ern.
0" +":
&ilent eplication of T&% Agents with 'ate !nset PrP-
res
1i.e c"urse -n-lyses ") in)ec+i&i+y +i+ers -n! PrP c"n&ersi"n -)+er br-in
in"cul-+i"n !e."ns+r-+e - clinic-lly silen+ $-se ") eG$"nen+i-l -*en+
re$lic-+i"n +-+ s+-r+s 6ell be)"re l-+e4"nse+ PrP4res $-+"l"*y. =n $-r+icul-r5
suc s+u!ies s"6 6y PrP4res is - $""r subs+i+u+e )"r Au-n+i+-+i&ely
-ssessin* -*en+ re$lic-+i"n. Hi*ure 1 s"6s eG$eri.en+-l !-+- )"r s(JI in
-.s+ers5
34
- s$ecies +-+ is Aui+e susce$+ible +" +is u.-n -*en+. =n
-.s+ers5 s(JI c-uses 6i!es$re-! br-in lesi"ns 120 ! -)+er ic in"cul-+i"n5
6ere-s 6+ .ice 6i+ s(JI -&e - 360 ! l-+ency 6i+ &ery li.i+e! lesi"ns.
35536

=n +e !-+- ") Hi*ure 1 +ere is - cle-r !isc"nnec+ be+6een +e +i.e -n!
sl"$es ") -ccu.ul-+in* -*en+ (s"li! re! line) &s. +"se ") PrP4res (blue br"7en
line). >"+e +e $r"*ressi&e l"* -ccu.ul-+i"n ") in)ec+i"us $-r+icles s+-r+in* -+
20 ! un+il - .-Gi.-l in)ec+i&i+y is re-ce! -+ 90 !. #*en+ -ccu.ul-+i"n is
+en -rres+e! -n! re.-ins -+ - $l-+e-u -s clinic-l si*ns be*in. 2"r+ly be)"re
-*en+ -rres+ -+ 90 !5 PrP4res be*ins +" )"r.5 -n! .-Gi.-l PrP4res (65Q ") +e
+"+-l br-in PrP) r-$i!ly c"inci!es 6i+ -*en+ -rres+. =n +e c-se ") PrP4res5
+ere is -n "bser&-ble 2 l"* rise ()r". 0.6 -+ 80 ! +" 60Q). 1e PrP4res s"6s
-n i!en+ic-l slee$ sl"$e 6en $l"++e! "n - l"* sc-le5 "r e&en eG+r-$"l-+e! +"
- le&el ") PrP4res +-+ is n"+ !irec+ly !e+ec+-ble. '"s+ si.$ly: (1) PrP4res
-$$e-rs -s - l-+e res$"nse +" i* le&els ") +e in)ec+i"us -*en+5 -n! (2) i*
PrP4res c-n -c+ -s $-r+ ") -n inn-+e i..une res$"nse +-+ li.i+s -*en+
re$lic-+i"n -n!%"r sur&i&-l. 1r-$$in* ") in)ec+i"us $-r+icles in - PrP4res
-.yl"i!
37
c-n be "ne un!erlyin* .ec-nis. )"r +is -rres+ (see +e sec+i"n
CPrP is - MeAuire! (ell 8in!in* 2i+e )"r =n)ec+i"us 123 P-r+iclesD).
Figure 1. @-.s+er s(JI $r"*ressi"n in !-ys $"s+4in)ec+i"n ic. 2u$eri.$"se!
!-+- )"r in)ec+i"us +i+er in l"*s (re! s"li! line) -n! Q PrP4res ") +e +"+-l PrP
(blue br"7en line). PrP is n"+ c"n&er+e! +" PrP4res un+il 80 !5 -n! PrP4res
s"6s - l-+e ...
0" +":
PrP-res $on7ersion Progresses at a ate ,ery "ifferent
from Agent
Hi*ure 1 -ls" !e."ns+r-+es .-+e.-+ic-lly i.$"r+-n+ !-+- +-+ -ll"6s "ne +"
c-lcul-+e -n! c".$-re +e !"ublin* +i.es ") -*en+ -n! PrP4res c"n&ersi"n.
1e e;ec+i&e ("bser&e!) !"ublin* +i.e (+i) by !e<ni+i"n inc"r$"r-+es b"+
re$lic-+i"n -n! eli.in-+i"n5
34
-n! c-n be -$$lie! +" - ."lecule -s 6ell -s -n
in)ec+i"us $-r+icle. 1e s(JI !"ublin* +i in -.s+ers is 7.6 !. =n .-r7e!
c"n+r-s+5 6en c-lcul-+e! by +is eAu-+i"n5 +e +i ") PrP4res in Hi*ure 1 is
0.116 !5 "r R65S *re-+er +-n +e -*en+ r-+e5 - cle-rly se$-r-+e $r"cess.
1is "bser&-+i"n uni<es .-ny !i&erse b-c+eri-l5 ye-s+ -n! 123 $r"+ein
-**re*-+i"n $en".en- bec-use si.il-r +y$es ") $r"+ein .is)"l!in* c-n
$r"*ress r-$i!ly e&en 6en ini+i-+e! by !i;eren+ +y$es ") $-s+ -n!
cu.ul-+i&e en&ir"n.en+-l s+resses. 1ese inclu!e +e .-ny +"Gic ce.ic-ls
+re-+.en+s +-+ in!uce in+r-cellul-r ye-s+ $r"+ein -**re*-+es5
38
in -!!i+i"n +"
+e 123 -n! c"n&en+i"n-l &ir-l in)ec+i"us -*en+s +-+ ul+i.-+ely in!uce PrP4
res -n! neur"<brill-ry +-n*le )"r.-+i"n res$ec+i&ely in n"n4!i&i!in*
.-..-li-n neur"ns.
39
Iisc"r!-n+ r-+es ") 123 -*en+ re$lic-+i"n -n! PrP4res c"n&ersi"n -re -
c"nsis+en+ )e-+ure ") 123s in 6+ -ni.-ls. 1is !isc"r!-nce -s n"+ been
"b&i"us in +e &ery s"r+ incub-+i"n 263L -.s+er scr-$ie ic ."!el (P65 ! +"
+er.in-l si*ns). @"6e&er5 -!!i+i"n-l ."!els 6i+ incub-+i"n +i.es ") R110 !
-ll !e."ns+r-+e - $r"*ressi&e sl"6 eG$"nen+i-l rise in in)ec+i&i+y )"ll"6e! by
- su!!en incre-se in PrP4res5 -s s"6n in Hi*ure 2 ") #si-+ic HE4(JI5 - s+r-in
+-+ is .uc ."re &irulen+ )"r 6+ .ice +-n s(JI. 1e HE4(JI -*en+ s+e-!ily
re$lic-+es by R4 l"*s ()r". P20 +" 90 !) be)"re $r"&"7in* - su!!en5 r-$i!
rise ") PrP4res in +e br-in.
40
>"+e +-+ +"+-l PrP (le)+ $-nel) re.-ins c"ns+-n+
-s i+s !eri&-+i&e PrP4res is bein* .is)"l!e! (TPL l-nes)5 i.e.5 PrP4res .is)"l!in*
is - $r"cess ") c"n&ersi"n r-+er +-n +rue re$lic-+i"n. '"re"&er5 - ne6
eG+re.ely )-s+ (9I -*en+ ."!el in b-n7 &"les5 6ic +-7es "nly 35 ! +"
+er.in-l !ise-se5
41
-ls" s"6s - .-r7e! !iscre$-ncy be+6een PrP4res -n!
in)ec+i"us +i+er. 1ese !ise-se! br-ins -&e i* le&els ") in)ec+i&i+y (8.4
l"*s%*.) bu+ "nly l"6 le&els ") PrP4res. 1" eG$l-in +is5 i+ is y$"+esi:e! +-+
(1) +ere -re !i;eren+ +"Gic -n! in)ec+i"us PrP4res )"r.s5 (2) +ese PrP )"r.s
re$lic-+e -n! .-+ure -+ !i;eren+ r-+es5 -n! (3) +e in)ec+i"us PrP4res subse+
c"n+-ins -!!i+i"n-l uniAue .is)"l!e! &-ri-n+s +-+ enc"!e -ll +e )-s+ -n!
sl"6 (9I s+r-ins in +ese &"les. >"+-bly5 b-n7 &"les -&e rele&-n+ -++ribu+es
bey"n! PrP. K) $-r+icul-r in+eres+ is +eir susce$+ibili+y +" .-ny !i;eren+ &ir-l
in)ec+i"ns5 -n! +eir -bili+y +" -c+ -s &ir-l reser&"irs in :""n"+ic in)ec+i"ns.
42

1ese &iruses .-y en-nce +e &irulence ") s".e (9I s+r-ins5 -s !"
re+r"&iruses )"r (9I in)ec+i"n in "+er r"!en+ cells (re&ie6e! in re).
21
). =+ is
-ls" $"ssible +-+ &"les c-rry s".e 123 s+r-ins -sy.$+".-+ic-lly -n! s$re-!
123s +r"u* +e en&ir"n.en+ &i- eGcre.en+5 -s +ey !" )"r "+er &iruses.
1e :""n"+ic s$re-! ") 123s is n"+ 6ell s+u!ie!5 -n! 123 c"nce$+s -n!
$re&en+i"n .-y be r-!ic-lly +r-ns)"r.e! by .e+-*en".ic -n-lyses.
Figure 2. ,-+e "nse+ ") PrP4res in HE4(JI 6+ .ice illus+r-+es c"ns+-n+ le&el ")
PrP in le)+ $-nel 6i+"u+ $r"+ein-se L (PL) )r". 50130 !. Mi*+ $-nel s"6s
+e HE4(JI -*en+ re$lic-+es by 5 l"*s in +ese .ice be)"re PrP4res is <rs+
!e+ec+-ble ...
0" +":
Agent-Induced Neurodegeneration "oes Not e9uire
PrP-res
'-r7e! neur"!e*ener-+i&e c-n*es c-n be ini+i-+e! by - 123 -*en+ 6i+"u+
$-+"l"*ic-l PrP4res -s -n -cc".$lice. 1is is 6ell !e."ns+r-+e! by +e &ery
$r"l"n*e! s(JI r-+ ."!el. M-+s in)ec+e! ic 6i+ s(JI -&e -n incub-+i"n +i.e
") R350 ! &s. -n incub-+i"n ") 120 ! in -.s+er s(JI. Me.-r7-bly5 in +ese
s(JI in)ec+e! r-+s5 cl-ssic-l 123 s$"n*i)"r. br-in c-n*es -n! 6i!es$re-!
.icr"*li-l -c+i&-+i"n bec".e $r".inen+ si.ul+-ne"usly -s .uc -s 100 !
be)"re PrP4res .-7es i+s en+r-nce.
23
=+ is ")+en -ssu.e! +-+ PrP4res is +e
c-use ") neur"n-l !e-+ in 123s5 bu+ +ese resul+s s"6 +-+ +e s(JI -*en+
i+sel) c-n $r"&"7e -c+i&e s$"n*i)"r. neur"!e*ener-+i"n 6i+"u+ -$$reci-ble
PrP4res5 $r"b-bly .e!i-+e!5 in $-r+5 by .icr"*li-. 1is +y$e ") !-+- .-7es i+
cri+ic-l +" c"nsi!er e-rly +er-$eu+ic in+er&en+i"ns -*-ins+ +e 123 -*en+5
r-+er +-n )"cusin* s"lely "n inibi+in* l-+e4s+-*e PrP4res )"r.-+i"n.
0" +":
A ole for PrP In %liminating Infectious Particles: with
Pathologic &e9uelae
1e $re!ic+i"n +-+ "s+ PrP4res c-n el$ li.i+ in)ec+i"n -s been &eri<e! by
recen+ 123 cul+ure eG$eri.en+s. #+ &ery e-rly $-ss-*es -)+er in)ec+i"n ")
neur"n-l 011 cells5 i* PrP4res le&els c"inci!e 6i+ li.i+in* 7uru -*en+
-ccu.ul-+i"n. ("n&ersely5 - !el-ye! l"6 le&el ") PrP4res +"ler-+es - 10004)"l!
i*er +i+er ") +e HE4(JI -*en+.
33
#n e&en ."re !r-.-+ic !e."ns+r-+i"n +-+
PrP4res c-n )unc+i"n +" eli.in-+e i* le&els ") -*en+ -s n"6 been
!e."ns+r-+e! in s+-+i"n-ry r-+ neur"n-l cell cul+ures in)ec+e! 6i+ HE4(JI.
H"ur l"*s ") in)ec+i"us -*en+ 6ere eli.in-+e! )r". cells !urin* - c"n+inuin*
en"r."us incre-se in +e $r"!uc+i"n ") b"+ PrP -n! PrP4res.
39
1is <n!in* is
c"n+r-ry +" +e $ri"n eG$ec+-+i"n +-+ PrP4res 6ill incre-se +e in)ec+i"us +i+er.
Hur+er."re5 +is n"n4in)ec+i"us PrP4res sel)4$er$e+u-+es5 un!ersc"rin* -
s+ress res$"nse -7in +" +e s+ress in!uce! b-c+eri-l el-b"r-+i"n ") bi"<l.
-.yl"i!s5
43
-s 6ell -s +" ye-s+ $r"+ein -**re*-+es in!uce! by en&ir"n.en+-l
ce.ic-ls.
38
2el)4$r"$-*-+in* PrP4res in +e cure! r-+ neur"ns is cle-rly -n
-.yl"i!"*enic $r"cess *"ne -6ry5 6i+ $"+en+i-l !es+ruc+i&e e;ec+s "n
neur"ns.
2yn+e+ic PrP4res $e$+i!es +-+ )"r. <brils c-n be +"Gic )"r neur"n-l +u."r
-n! cerebell-r *r-nule cells.
44
Kn +e "+er -n!5 -bun!-n+ in+r-cellul-r PrP4
res -.yl"i! <brils in!uce! by scr-$ie -n! (JI -*en+ in)ec+i"n -re insuBcien+
+" c-use &isible !e*ener-+i&e "r +"Gic c-n*es in neur"n-l 011 cells.
45
1us
(1) in)ec+e! neur"n-l cells l-c7 - s$eci-l +"Gic )"r. ") PrP4res
46
"r (2) "+er
cellul-r )-c+"rs -n! cell +y$es (suc -s -c+i&-+e! .icr"*li- -n! -s+r"cy+es) -re
reAuire! )"r s$"n*i)"r. c-n*e. 8ec-use 011 cells in cul+ure c"n+-in &ery
i* le&els ") +e in)ec+i"us -*en+ (U3 in)ec+i"us $-r+icles $er cell)5 bu+ s"6
n" +"Gic c-n*es5 n"n4neur"n-l cells in +e br-in -re li7ely +" be $-r+ ") +e
$r"*ressi&e 123 neur"!e*ener-+i&e c-sc-!e in &i&"5 "ne +-+ $r"b-bly s+-r+s
-s - "s+ !e)ensi&e .ec-nis..
1e re-li:-+i"n +-+ PrP4res is - l-+e res$"nse +" e-rlier -*en+4in!uce!
s+resses -s rele&-nce )"r #I -n! "+er n"nin)ec+i"us !e*ener-+i&e br-in
!ise-ses. =n #I5 $-s+ in)ec+i"us insul+s5 in c"nFunc+i"n 6i+ cu.ul-+i&e
en&ir"n.en+-l s+resses -n! +"Gins5 .-y ul+i.-+ely c-use +e l-+e s+-*e
$r"+ein .is)"l!in* ") J4-.yl"i! -n! 1-u $-+"l"*y. 1e $r"*ressi&e
-ccu.ul-+i"n ") PrP -.yl"i!5 e&en -)+er +e 123 -*en+ -s been eli.in-+e!
)r". cells5
39
*i&es )ur+er cre!ence +" sel)4$er$e+u-+in* $-+"l"*ic-l $r"+ein
.is)"l!in* in l-+er $r"*ressi&e s+-*es ") neur"!e*ener-+i&e !ise-ses. =n!ee!5
+is is 6en n"n4in)ec+i"us see!e! -.yl"i! c"n&ersi"ns -re ."s+ rele&-n+5 -s
"ri*in-lly $r"$"se!.
47
0" +":
Innate Immune ecognition of Agent !ccurs %arly in
Infection
=n 123s5 - r"le )"r +e i..une sys+e. -s been l-r*ely !is.isse! bec-use n"
-cu+e ly.$"cy+ic in<l+r-+es -n! neu+r-li:in* -n+ib"!ies -re seen.
>e&er+eless5 .-ny cl-ssic-l eG$eri.en+s in scr-$ie -n! (JI )r". 19601990
cl-ri<e! +e cri+ic-l i.$"r+-nce ") ly.$"re+icul-r +issues -n! .yel"i! 6i+e
bl""! cells in +e !isse.in-+i"n -n! seAues+r-+i"n ") 123 -*en+s in $eri$er-l
+issues5
37
- r"u+e +-+ .-ny &iruses +-7e 6i+in .i*r-+"ry ly.$"re+icul-r
cells +" esc-$e -n+ib"!y rec"*ni+i"n. '"re cri+ic-lly5 1-+eisiOs *r"u$ <rs+ use!
i..un"!e<cien+ 2(=I .ice +" $r"&e +-+ +e ly.$"re+icul-r sys+e. 6-s
reAuire! )"r e;ec+i&e s$re-! -n! $ersis+ence ") scr-$ie $eri$er-lly.
48

#!!i+i"n-l 1* ."!els -&e subs+-n+i-+e! +is in b"+ scr-$ie -n! (JI.
@"6e&er5 1* ly.$"re+icul-r -bl-+i"ns "nly re+-r! !ise-se "nse+ bec-use
-ni.-ls ul+i.-+ely succu.be! +" V"ri! in)ec+i"us !ise-se.
49550
9i+ +e
-cce$+-nce ") +e in)ec+i"us PrP "r $ri"n y$"+esis5 i+ 6-s )ur+er -ssu.e!
+-+ 123 -*en+s 6"ul! $r"&"7e n" i..une res$"nse bec-use PrP is n"+
rec"*ni:e! by i+s "s+ -s )"rei*n. @"6e&er5 +e e-rly .icr"*li-l -c+i&-+i"n in
r-+ s(JI
23
rene6e! in&es+i*-+i"ns ") inn-+e i..une res$"nses +-+ .i*+
."!ul-+e -*en+ re$lic-+i"n -n! l-+ency. H"r +ese s+u!ies5 i+ 6-s
-!&-n+-*e"us +" use n"r.-l 6+ .ice bec-use ") +eir 6ell c-r-c+eri:e!
i..une sys+e.s.
'-ny $-+"*enic .icr"bes5 )r". s.-ll &iruses +" .yc"b-c+eri-5 -re
seAues+ere! in - l-+en+ s+-+e in .yel"i! !en!ri+ic cells5 -n! $ysi"l"*ic
s+resses $r"&"7e +eir recru!escence -n! !isse.in-+i"n. 1is $-++ern <+s +e
1030 y !"r.-ncy -n! recru!escence ") b"+ i-+r"*enic s(JI -n! 7uru
-*en+s in u.-ns. 1is $r"cess is -ls" -$$-ren+ in +e .uc s"r+er HE4(JI
."use ."!el in )"ur res$ec+s. Hirs+5 is"l-+e! br-in .icr"*li-5 - rel-+i&e ")
$eri$er-l .i*r-+"ry !en!ri+ic cells5 c"n+-in eG+re.ely i* le&els ") +e HE4
(JI -*en+5 bu+ .inu+e -."un+s ") PrP5 -n! n" !e+ec+-ble PrP4res (re&ie6e! in
re).
11
). 2ec"n!5 -rr-y s+u!ies ") rele&-n+ ."lecul-r .-r7ers !e."ns+r-+e!
inn-+e i..une res$"nses in in)ec+e!5 bu+ n"+ c"n+r"l .icr"*li-. '"re"&er5
+is s$eci<c *r"u$ ") .yel"i! cell +r-nscri$+s -re subs+-n+i-lly ele&-+e! in HE4
(JI in)ec+e! .icr"*li-5 bu+ -re n"+ e!uce! by PrP4res.
51
1ir!5 s".e ") +ese
inn-+e i..une +r-nscri$+s -re $r"&"7e! !urin* +e e-rlies+ $-se ")
eG$"nen+i-l -*en+ re$lic-+i"n5 6ell be)"re PrP4res "r neur"!e*ener-+i&e
c-n*es be*in.
40
1ese inn-+e i..une .-r7ers cle-rly si*ni)y "s+4
rec"*ni+i"n ") - )"rei*n in)ec+i"us $-r+icle r-+er +-n "s+ PrP4res.
2ubseAuen+ s+u!ies -&e unc"&ere! -!!i+i"n-l i.$"r+-n+ e-rly "s+ inn-+e
i..une res$"nses in scr-$ie5
52
!e."ns+r-+in* +ese res$"nses -re - *ener-l
)e-+ure ") 123 in)ec+i"ns. H"ur+5 i* scr-$ie in)ec+i"us +i+ers -&e been
)"un! in is"l-+e! $eri$er-l $l-s.-cy+"i! !en!ri+ic cells +-+ l-c7 -ny
!e+ec+-ble PrP.
53
1is )ur+er eG+en!s +e cen+r-li+y ") +ese +y$es ") cells in
123 -*en+ l-+ency -n! +issue s$re-!. =+ -ls" su**es+s +-+ PrP .-y n"+ be -n
essen+i-l "r in+e*r-l c".$"nen+ ") +e .ini.-l in)ec+i"us $-r+icle. =+ is -ls"
uncle-r "6 PrP4res5 - see! )"r i+s "6n c"n&ersi"n5 c"ul! -rres+ i+sel) )"r
ye-rs5 -n! +en re-c+i&-+e by see!in* i+sel) in s$eci-li:e! !en!ri+ic cells +-+
c"n+-in n" !e+ec+-ble PrP.
0" +":
Proof That an AnimalKs Innate Immune (iochemical
&ystems 'imit Agent %8pansion
1e -b"&e "bser&-+i"ns s+r"n*ly i.$lic-+e c".$leG cellul-r res$"nses +" -
)"rei*n -*en+ +-+ -re unrel-+e! +" ei+er PrP "r PrP4res c"n&ersi"n. =+ -s
l"n* been 7n"6n +-+ PrP i+sel) is insuBcien+ +" .-7e cells susce$+ible +"
in)ec+i"n since -n -ni.-lOs lun* -n! 7i!ney e$i+eli-l cells 6i+ PrP !" n"+
n"r.-lly bec".e in)ec+e!. 1us in!i&i!u-l cell -n! c".$leG -ni.-l res$"nses
-re in&"l&e!. 1e cri+ic-l r"le ") -n -ni.-lOs cellul-r !e)ense .ec-nis.s
-*-ins+ 123 -*en+s -s n"6 been c"nclusi&ely !e."ns+r-+e!. 8-sic-lly5 6en
*r"6n in cul+ure5 123 -*en+s -re rele-se! )r". .ul+icellul-r su$$ressi&e "s+
c"n+r"ls. 1us 123 -*en+s -re )ree! +" re$lic-+e r-$i!ly5 -n! s".e -*en+s5 -s
HE4(JI5 -cie&e e&en i*er +i+ers $er cell +-n in br-in. ("n&ersely5 6en
+ese cul+ure! -*en+s -re re4in"cul-+e! ic5 +ey c-n n" l"n*er re$lic-+e
r-$i!ly5 i.e.5 +ey -re -*-in c"ns+r-ine! by c".$leG "s+ c"n+r"ls +-+ c-n
+-r*e+ b"+ re$lic-+i"n -n! !es+ruc+i&e $r"cesses. Hi&e &ery !i;eren+ scr-$ie
-n! u.-n 123 -*en+s 6i+ 6i!ely !i&erse +i e;ec+i&e !"ublin* +i.es )r".
4.3 +" 32 ! in 6+ .ice -ll su!!enly -n! !r-.-+ic-lly re!uce! +eir !"ublin*
+i.e +" - +i ") 1 ! 6en *r"6n in 011 neur"n-l cells.
33
1us -ll +ese !i;eren+
123 -*en+s -re c-$-ble ") r-$i! re$lic-+i"n 6en rele-se! )r". .ul+icellul-r
"s+ c"n+r"ls. M-$i! -*en+ re$lic-+i"n !i! n"+ !e$en! "n PrP4res
-ccu.ul-+i"ns bec-use PrP4res in cul+ure s$-nne! )r". 0Q +" 50Q. 9en
r-$i!ly re$lic-+in* (JI -n! scr-$ie -*en+s in cul+ure 6ere re4in"cul-+e! in
.ice5 +ey recre-+e! +eir s+r-in4s$eci<c re*i"n-l neur"$-+"l"*y in -!!i+i"n
+" +eir "ri*in-l !is+inc+i&e l"n* l-+encies.
54555
1us +e re$lic-+i"n -n! sur&i&-l
") +ese -*en+s -re cle-rly li.i+e! by cells -n! )-c+"rs n"+ $resen+ in
."n"+y$ic cul+ure. 1is !-+- s"6s n" e&i!ence )"r -*en+ .u+-+i"ns -s +e
c-use ") +is c-n*e. '"re"&er5 .ice cle-rly c-n res$"n! +"5 -n!
!i;eren+i-lly re+-r! e-c ") +ese -*en+s.
#+ - sin*le cell le&el5 inn-+e i..uni+y -ls" .-7es cells $er.issi&e )"r
$-r+icul-r -*en+s. -n! e&en cells in cul+ure +-+ syn+esi:e i* le&els ")
"."l"*"us PrP c-n resis+ in)ec+i"n )"r un7n"6n re-s"ns. >eur"bl-s+".-
(>2-) +u."r cells use! )"r .-ny scr-$ie s+u!ies -re 7n"6n +" be *ene+ic-lly
uns+-ble5 -n! ine&i+-ble $r"*ressi&e $"$ul-+i"n &-ri-n+s -re !i;eren+i-lly
rece$+i&e +" e&en - sin*le -*en+ s+r-in5 suc -s 22, scr-$ie.
56
@ence5 i+ 6ill be
uncle-r i) re$lic-+i"n "r l"ss ") - *i&en 123 -*en+ is !ue +" -l+ere! cell
c-r-c+eris+ics "r .u+-n+ s+r-ins. 1e $"si+i&e in)ec+i"n ") *ene+ic-lly s+-ble
011 cells 6i+ &ery !i;eren+ -*en+s -ll"6e! us +" !e."ns+r-+es +-+ +ese
cells eG &i&" c-n !i;eren+i-lly rec"*ni:e -n! su$$ress +ese -*en+s +"u*
+eir inn-+e i..une ne+6"r7s. 011 cells5 6i+ +eir in&-ri-n+ PrP -n! cell
$en"+y$e5 cle-rly s"6 in+rinsic $re)erences )"r $-r+icul-r 123 -*en+s.
22

2ince 011 cells -re $er.issi&e )"r in)ec+i"n by -ll +ese -*en+s +ey !" n"+
reAuire -!!i+i"n-l )-c+"rs. =ns+e-!5 i+ is e&i!en+ +-n -c+i&e cellul-r $r"cess
c-n li.i+ in)ec+i"n -n! e&en le-! +" - $r"*ressi&e cure. H"r eG-.$le5 +e
.urine -!-$+e! 7uru -*en+ re$r"!ucibly -n! s+-bly re$lic-+es )"r R1 y -+ -
c"ns+-n+ le&el5 -n! c"n+inues +" elici+ l-r*e -."un+s ") PrP4res. We+5 -s n"+e!5
+is -*en+ -++-ins -n in)ec+i"us +i+er +-+ is "nly 1%1000+ ") +e .urine
-!-$+e! HE4(JI -*en+.
33
'"re"&er5 .urine -!-$+e! &(JI is -ble +" in)ec+
$-r-llel 011 cells5 -n! in!uce &(JI4s$eci<c PrP4res b-n!s )"r P9 $-ss-*es (3
4 6ee7s). @"6e&er5 in +is c-se5 PrP4res !i.inises "&er +e neG+ )e6 6ee7s
-n! ul+i.-+ely is un!e+ec+-ble (6i+ n" c-n*e in +e +"+-l cell PrP). 1is
su**es+s +ese 011 cells -&e subs+-n+i-lly cure! +e.sel&es ") +e &(JI
-*en+. 9e -&e re$e-+e! +is "bser&-+i"n R5 +i.es5 usin* !i;eren+ &(JI
in)ec+e! ."use br-in s-.$les -n! !i;eren+ $-ss-*es ") 011 cells (,iu5
1i++.-n5 Li$7"rir5 8"+si"s5 -n! '-nueli!is5 un$ublise! !-+-). (le-rly +is
-*en+ re!uc+i"n (-ls" s"6n by - re$resen+-+i&e in)ec+i"us -ss-y) in&"l&es -n
-c+i&e inn-+e !e)ense $r"cess +-+ is -*en+4s$eci<c5 r-+er +-n - l-c7 ")
s".e )-c+"r necess-ry )"r in)ec+i"n. 2".e ") +ese !i;eren+i-l in+rinsic cell
c"n+r"ls .-y be unc"&ere! by i* +r"u*$u+ M># in+er)erence screens.
=n!ee!5 ini+i-+i&es +-+ +-r*e+ +ese n"n4PrP )-c+"rs s"ul! be ") &-lue in
-rres+in* -n! +re-+in* (JI.
0" +":
PrP is a e9uired $ell (inding &ite for Infectious T&%
Particles
PrP is - 0P= -nc"re! $r"+ein -n! is ul+r-s+ruc+ur-lly -bun!-n+ "n $l-s.- -n!
3M .e.br-nes.
45
9ile "+er .e.br-ne ."lecules -n! cellul-r .-cinery
-re li7ely +" !ri&e PrP4res -ccu.ul-+i"n in +e li&in* cell5 i+ is cle-r )r". PrP
7n"c7"u+ s+u!ies +-+ "s+ PrP is essen+i-l )"r $r"*ressi&e scr-$ie -*en+
in)ec+i"n.
57
Kne in+er$re+-+i"n ") +ese !-+- $"si+s +-+ s".e )"r. ") PrP
.us+ be +e in)ec+i"us -*en+. #l+ern-+i&ely5 "s+ PrP c-n be - rece$+"r -n!%"r
sc-;"l! reAuire! )"r -c+i&e -*en+ re$lic-+i"n -n! s$re-!. 1is l-++er &ie6 is
b-se! "n es+-blise! &ir-l reAuire.en+s )"r - $-r+icul-r "s+ $r"+ein5 6ere
e&en - sin*le c"!in* .u+-+i"n in +e "s+ rece$+"r c-n $re&en+
in)ec+i"n.
47
Hi*ure 3# !i-*r-.s +e PrP null s+-+e 6en +ere is n" sc-;"l! )"r
e;ec+i&e 123 -*en+ re$lic-+i"n. @ence -*en+ $-r+icles !isin+e*r-+e -n! -re
eli.in-+e!. Hi*ure 38 s"6s in)ec+i"n 6i+ +6" !i;eren+ 123 in)ec+i"us
-*en+s5 e-c in!ucin* - rec"*ni:-bly !i;eren+ PrP4res -.yl"i! -**re*-+e. =n
Hi*ure 3(5 se$-r-+e $r"cesses ") -*en+ re$lic-+i"n -n! PrP4res -**re*-+i"n
-re !i-*r-..e!5 inclu!in* +r-$$in* ") s".e -*en+ by PrP -.yl"i!. 9ile
+ere is - cle-r !is+inc+i"n be+6een +e in)ec+i"us -n! +e $urely *ene+ic
c-uses ") PrP $-+"l"*y5 b"+ c-n in!uce +r-ns.e.br-ne )"r.s ") PrP +-+
le-! +" lys"s".-l $r"cessin* -n! -.yl"i! $l-Aue !e$"si+i"n.
58
Figure 3. '"!el ") in&-!in* P25 n. 123 &ir-l $-r+icle bin!in* i+s reAuire!
"s+ PrP rece$+"r +" in!uce PrP4res -.yl"i!. (A) 2"6s !isin+e*r-+i"n -n!
eli.in-+i"n ") +e in)ec+i"us $-r+icle 6i+ i+s nucleic -ci! c"re (s"li! circle)
-n! $r"+ec+i&e ...
'"s+ s+r-ins (-s s+r-in #) in!uce -n i!en+ic-l PrP4res b-n! $-++ern5 $r"&i!e!
+-+ +e cell +y$e -n! s$ecies -re n"+ &-rie!. =n !i;eren+ s$ecies -n! cell
+y$es +e PrP b-n! !i;erences -re l-r*ely !ue +" $"s+4+r-nsl-+i"n-l
*lyc"syl-+i"n5 -n! !e*lyc"syl-+i"n 6i+ neur-.ini!-se re&e-ls +e un!erlyin*
"."*enei+y ") PrP5 <rs+ s"6n by res"lu+i"n ") - sin*le !iscre+e is"elec+ric
s$"+ in 2I *els.
59
3&en ."re eG+ensi&e !e*lyc"syl-+i"n +-+ )ur+er .ini.i:es
PrP &-ri-+i"n !"es n"+ re!uce in)ec+i&i+y "r -l+er +e s+r-inOs l-+ency -n!
neur"$-+"l"*ic $en"+y$e.
37
>e&er+eless5 6e -! $r"$"se! +-+ - r-re "r
unusu-l -*en+ (s+r-in 8) .i*+ bin! PrP !i;eren+ly +" yiel! - &-ri-n+ PrP4res
b-n! $-++ern +-+ is .-in+-ine! in &-ri"us s$ecies -n! cell +y$es5 re*-r!less
") *lyc"syl-+i"n !i;erences.
47
1is -s n"6 been &eri<e! eG$eri.en+-lly. 1e
PrP4res !"uble+ in!uce! by +e uniAue 823%&(JI -*en+ is c"ns+-n+ in in)ec+e!
c"6s5 u.-ns5 6+ .ice5 -n! e&en in ."n"+y$ic cell cul+ures.
22
=n c"n+r-s+5
."s+ "+er (JI -n! scr-$ie s+r-ins -&e n"6 been c"nclusi&ely s"6n +"
in!uce in!is+in*uis-ble PrP4res b-n!s in s+-n!-r! 6+ ."use br-ins.
36
1is
in&i+es )ur+er Aues+i"ns )"r $ri"n $r"$"nen+s -b"u+ 6-+ "bser&-ble PrP
!i;erences .i*+ enc"!e s+r-ins.
# PrP rece$+"r ."!el <+s .-ny i.$"r+-n+ 123 )e-+ures5 inclu!in* +e s$ecies
C+r-ns.issi"n b-rrierD lin7e! +" "s+ PrP c"!"n .u+-+i"ns. =+ -ls" -cc"un+s )"r
+e -b"&e re+rie&-l ") - bi"l"*ic-lly i!en+ic-l 123 -*en+ )r". cells 6i+
!i;eren+ PrP4res b-n!s -n! PrP *lyc"syl-+i"n $-++erns. PrP4res $-++erns -re
&ery !i;eren+ in ly.$"i! +issues5 br-in5 -n! cul+ure! cells5 bu+ -ll +ese cells
yiel! +e s-.e -*en+ r-+er +-n in!i&i!u-lly !is+inc+ s+r-ins. #cc"r!in* +" +e
$ri"n c"nce$+ -+ le-s+ s".e ") +ese !i;eren+ PrP )"r.s s"ul! enc"!e
&-ri"us 123 s+r-ins. Ies$i+e in+ense e;"r+s5 nei+er - re$r"!ucibly in)ec+i"us
n"r - s+r-in4enc"!in* PrP c"n)"r.er -s been i!en+i<e!. =n su.5 !i;eren+
-*en+ s+r-ins *i&e +e s-.e PrP4res $-++ern5 -n! s-.$les 6i+ &ery !i;eren+
PrP4res $-++erns5 e&en )r". !i;eren+ s$ecies5 c-n $r"$-*-+e +e s-.e
in)ec+i"us -*en+.
1e c"nce$+ +-+ PrP is - reAuire! 123 -*en+ rece$+"r5 r-+er +-n +e c-us-l
in)ec+i"us -*en+5 -s recei&e! li++le -++en+i"n. @"6e&er5 recen+ s+u!ies s"6
+-+ PrP is in+i.-+ely in&"l&e! in +e li)e cycle ") "+er in)ec+i"us -*en+s5 )r".
&iruses +" *r-.4ne*-+i&e b-c+eri-.
60561
=n!ee!5 PrP is +e rece$+"r reAuire! )"r
- b-c+eri-l "r-l in)ec+i"n5 -n! +is <n!in* $-r-llels +e PrP reAuire.en+ by
123 -*en+s )"r in)ec+i"n. #n incre-se in PrP5 e&en 6en i+s seAuence !"es n"+
.-+c +e PrP ") +e in)ec+e! !"n"r5 .-r7e!ly )-cili+-+es in)ec+i"n ") u.-n
-*en+s +" .ice. =n )-c+5 1* .ice "&ereG$ressin* 6+ .urine PrP -re ."re
susce$+ible +" u.-n &(JI +-n 1* .ice "&ereG$ressin* u.-n PrP.
22
1is
<n!in* is c".$-+ible 6i+ PrP -s - rece$+"r5 e&en i) sli*+ly V-6e!5 bu+ is
c"n+r-ry +" +e $ri"n !"*.- +-+ PrP seAuence !i;erences 6ill necess-rily
+6-r+ cr"ss4s$ecies in)ec+i"n. # &ir-l in!uc+i"n ") $-+"l"*ic-l $r"+ein
-**re*-+es5 inclu!in* u.-n $-r-.yG"&irus in!uce! neur"!e*ener-+i&e
neur"<brill-ry +-n*les5
39
-ls" *i&es $rece!ence +" 123 -*en+ in!uce! PrP4res5
-s !"es +e ne6es+ !e."ns+r-+i"n +-+ - &ir-l in)ec+i"n c-n in!uce -
c"n)"r.-+i"n-l C$ri"n4li7eD s+-+e in .i+"c"n!ri-l .e.br-ne c".$leGes
('#V2).
62563
1is l-s+ $-r-llel is e&en ."re in+ri*uin* bec-use '#V2 -c+i&-+e
-n! $r"$-*-+e -n+i&ir-l inn-+e i..une res$"nses5 - <n!in* re.-r7-bly
c"nsis+en+ 6i+ +e inn-+e i..une res$"nses in 123s re&ie6e! -b"&e. 2uc
<n!in*s )ur+er su$$"r+ +e ."!el in Hi*ure 38 6ic s"6s - 123 &ir-l
$-r+icle +-+ in!uces PrP4res -**re*-+i"n by bin!in* i+s reAuire! "s+
rece$+"r.
47
0" +":
The 3unction<s= and 'ocation of PrP are Ad7antageous
for T&% Agents
#l+"u* i+ is ")+en s+-+e! +-+ +e n"r.-l )unc+i"n ") PrP is un7n"6n5 PrP is
cle-rly in&"l&e! in +er.in-l neur-l !i;eren+i-+i"n5 cell4+"4cell c"n+-c+s5 -n!
syn-$se )"r.-+i"n (re&ie6e! in re).
39
). >e6ly )"r.e! n-n"+ubes $r"li)er-+e
-s PrP is in!uce! in cul+ure! neur"ns un!er*"in* +er.in-l !i;eren+i-+i"n5 -n!
n-n"+ubes )-cili+-+e +e +r-ns.issi"n ") &iruses. =n!ee!5 +e $r"li)er-+i"n ")
PrP ric n-n"+ubes resul+ in R1204)"l! incre-ses in 123 in)ec+i"us $-r+icles
$er cell.
39
8ec-use PrP is n"+ essen+i-l )"r +e n"r.-l )unc+i"n ") -n -ni.-l5
123 -*en+ bin!in* +" "s+ PrP5 es$eci-lly -+ l"6er -sy.$+".-+ic le&els5 6ill
n"+ resul+ in l"ss ") -ny cri+ic-l $ysi"l"*ic-l )unc+i"n. #*en+ iF-c7in* ") PrP
+us $r"&i!es )"r l"n*4+er. sur&i&-l ") b"+ +e -*en+ -n! +e -ni.-l. 9en
PrP bin!s +e in)ec+i"us $-r+icle5 i+ c-n -ls" el$ +e -*en+ i!e )r". -!-$+i&e
i..une sur&eill-nce. #!!i+i"n-lly5 PrP4res -.yl"i! +r-$$in* in .yel"i!
!en!ri+ic cells
26
-n! .-cr"$-*es c-n s+ruc+ur-lly $r"+ec+ +e -*en+ )r".
eli.in-+i"n )"r .-ny ye-rs5 $-r+icul-rly bec-use PrP4res5 -s "+er -.yl"i!s5
-re s" i.$ene+r-ble -n! ins"luble. Hin-lly5 -$$"se! $l-s.- .e.br-nes
be+6een +6" cells -re 7n"6n +" eGc-n*e ."lecul-r c".$"nen+s5 -n! +us
-*en+ -++-c.en+ +" PrP 6ill )ur+er )-cili+-+e cell4+"4cell s$re-!5 +e i*ly
)-&"re! r"u+e )"r 123 -*en+s.
55
K+er PrP )unc+i"ns .-y c"n)er -!!i+i"n-l
-!&-n+-*es.
0" +":
T&% Infections with 6 &trains &hare 3eatures with 2east
LPrionsM
Hi*ure 38 -ls" $re!ic+s +-+ +6" !i;eren+ -*en+ s+r-ins5 e-c in!ucin*
rec"*ni:-bly uniAue $-+"l"*ic-l PrP4res b-n!s5 c"ul! eGis+ in +e s-.e cell.
=n +e $ri"n ."!el5 i+ is cl-i.e! +-+ -n in+er.e!i-+e PrP4res ci.er- (") +6"
!i;eren+ PrP c"n)"r.ers) 6ill .-+eri-li:e5 -n! *i&e rise +" in+er.e!i-+e
in)ec+i"us $r"$er+ies5 -s $r"$"se! )"r -!-$+i&e cr"ss4s$ecies PrP4res
c"n&ersi"ns.
28
=n c"n+r-s+5 in +e Hi*ure 3 &ir-l ."!el5 +6" !i;eren+ 123
-*en+s 6"ul! c"n+inue +" in!uce in!e$en!en+ # -n! 8 )"r.s ") PrP4res5 i.e.5
+6" in)ec+in* s+r-ins 6"ul! .-in+-in +eir in!e$en!en+ i!en+i+ies5 -n! e-c
PrP4res 6"ul! c"n+inue +" see! i+sel) -n! -ccu.ul-+e in +e cell. =n )-c+5 +6"
(JI s+r-ins -&e been s"6n +" si.ul+-ne"usly re$lic-+e in -ni.-ls )"r 400 !5
-n! e-c .-in+-ins i+s "ri*in-l s+r-in $en"+y$e.
11
'"re"&er5 +6" !i;eren+
-*en+s in!ucin* +6" !i;eren+ PrP4res c"n)"r.ers c-n -ccu.ul-+e in - 011
cell 6i+ n" e&i!ence )"r -ny ci.eric PrP4res in+er.e!i-+e.
55
1is l-++er
"bser&-+i"n $-r-llels ye-s+ C$ri"nD -.yl"i! s+u!ies +-+ -ls" s"6 +6"
!i;eren+ +y$es ") $r"+ein -**re*-+es c-n eGis+ in +e s-.e cell. =n ye-s+ cells
+ese !i;eren+ cy+"$l-s.ic -**re*-+es -re .iGe! by -seGu-l .-+in*5 - n"n4
'en!eli-n *ene+ic $r"cess
38
&ery !i;eren+ )r". in)ec+i"ns ") .-..-ls 6i+
+issue4s$eci<c -*en+ +-r*e+in* -n! s$re-!. Kn +e "+er -n!5 i) "ne i*n"res
+e Cin)ec+i"usD !esi*n-+i"n )"r ye-s+ $ri"ns5 b"+ ye-s+ -n! .-..-li-n
-.yl"i!s s"6 - s+ri7in* -bili+y +" sel)4$r"$-*-+e +eir in!i&i!u-l
c"n)"r.-+i"ns5 $"ssibly by usin* - si.il-r ne+6"r7 ") cell $-+6-ys -n!
.ec-nis.s.
=n+eres+in*ly5 !i;eren+ +y$es ") ye-s+ $r"+ein -**re*-+es c-n $r"."+e "r
inibi+ e-c "+erOs -$$e-r-nce -n! .-in+en-nce.
64
=n c"n+r-s+5 -n inibi+in*
123 in)ec+i"us -*en+5 bu+ n"+ PrP4res -**re*-+es5 is reAuire! +" $re&en+
su$erin)ec+i"n by - sec"n! -*en+.
55
1is is rele&-n+ )"r u.-n in)ec+i"ns
bec-use &-ccin-+i"n ") .ice 6i+ l"6 le&els ") +e -&irulen+ s(JI -*en+ c-n
c".$le+ely $re&en+ su$erin)ec+i"n by +e ."re &irulen+ HE4(JI s+r-in 6i+"u+
+e $r"!uc+i"n ") -ny !e+ec+-ble PrP4res (re&ie6e! in re).
11
). 1e $resence ")
!i;eren+ +y$es ") !i-*n"s+ic -.yl"i! in - cell -s -!!i+i"n-l rele&-nce )"r
u.-n !ise-se. #.yl"i!s n"+ lin7e! +" - 7n"6n in)ec+i"us s"urce c-n c"4eGis+
6i+ +"se $r"&"7e! by - 123 -*en+. P"si+i&e seri-l +r-ns.issi"n ") s(JI +"
-.s+ers 6-s "b+-ine! )r". - br-in 6i+ .-ny cl-ssic-l #I J4-.yl"i!
$l-Aues in -!!i+i"n +" s$"n*i)"r. c-n*es -n! PrP4res +y$ic-l )"r s(JI
('-nueli!is5 un$ublise! !-+-). >ei+er -.yl"i! inibi+e! +e "+er.
0" +":
&tability: %7olution: and &election of T&% Agent &trains
=n *ener-l5 123 -*en+s c-n s"6 - re.-r7-ble l-c7 ") c-n*e5 e&en 6en
$-ss-*e! +r"u* !i;eren+ s$ecies. 3-c -*en+ s+r-in5 6e+er u.-n "r
see$ !eri&e!5 *i&es - c-r-c+eris+ic incub-+i"n +i.e -n! neur"-n-+".ic-l
lesi"n $r"<le in - *i&en s$ecies.
22
Hi*ure 4 is - c".$"si+e ") $ublise!
eG$eri.en+-l !-+- s"6in* rele&-n+ incub-+i"n +i.e )e-+ures )"r u.-n 123
is"l-+es in r"!en+s. Hirs+5 in seAuen+i-l ic $-ss-*es5 +ere is - $r"*ressi&e
re!uc+i"n in incub-+i"n +i.e !en"+in* -n incre-se! -*en+ &irulence )"r +e
reci$ien+ s$ecies. Iurin* +is e&"l&in* -*en+ -!-$+-+i"n5 +e PrP4res b-n!
$-++ern !"es n"+ c-n*e. 1ese )un!-.en+-l -n! $r"*ressi&e -*en+ c-n*es
-re c"nsis+en+ 6i+ 7n"6n &ir-l -!-$+-+i"n +r"u* nucleic -ci! .u+-+i"n5 "r
selec+i"n )r". - .iG+ure ") rel-+e! -*en+ s+r-ins.
23
=n c"n+r-s+5 - si.il-r
$r"*ressi&e -*en+ c-n*e )r". $1 +" $2 is n"+ "bser&e! -)+er ic in"cul-+i"n ")
recPrP4res -.yl"i!.
65
2ec"n!5 +e s-.e -*en+ in - !i;eren+ s$ecies c-n*es
i+s incub-+i"n (e;ec+i&e !"ublin*) +i.e5 e.*.5 s(JI in r-+s5 6+ .ice (6+4'")5
*uine- $i*s (0P)5 -n! -.s+ers (@-) -s s"6n in Hi*ure 4. 1is in!ic-+es
s$ecies4s$eci<c !e)enses )"r - *i&en -*en+5 -s !iscusse! -b"&e. 1e *r-$ ")
&(JI in 6+ .ice -ls" !e."ns+r-+es - &ery !i;eren+ incub-+i"n $-++ern )r".
s(JI5 -n! -!!i+i"n-l !is+inc+i"ns -re "b&i"us 6i+ +e (-n!ler (M',) -n! 22,
scr-$ie s+r-ins in s+-n!-r! 6+ .ice.
22
1us e-c incub-+i"n +i.e $-++ern is
!e+er.ine! by +e -*en+5 -n! n"+ by +e in&-ri-n+ .urine 6+ PrP5 "r in!ee!5
by -ny +e "+er i!en+ic-l b-c7*r"un! *enes. Me.-r7-bly5 +e &(JI -*en+
-$$e-rs s" !".in-n+ +-+ i+ -ls" *i&es -n i!en+ic-l s+r"n* y$"+-l-.ic
+-r*e+in* $-++ern in .ice5 e&en -)+er l"n*4+er. re$lic-+i"n in c"6s (823) "r in
u.-ns (&(JI) 6i+ !i;eren+ PrP seAuences.
22
1ir!5 !es$i+e *r"6+ in -
e+er"l"*"us s$ecies5 123 -*en+s c-n re+-in +eir -bili+y +" in)ec+ +eir !"n"r
s$ecies 6i+ +eir "ri*in-l $en"+y$e5 e.*.5 -.s+er s(JI +r-ns.i++e! +" .ice
bec".es &ery $r"l"n*e!5 ye+ e&en -)+er seri-l ."use $-ss-*es +is s(JI
-*en+ s+ill re+-ins i+s -bili+y +" i..e!i-+ely re$lic-+e r-$i!ly in -.s+ers (re!
-rr"6).
66
1is in!ic-+es b"+ +e $reser&-+i"n ") -n in&-ri-n+ s+r-in4s$eci<c
)e-+ure5 -s 6ell -s - .u+-ble )e-+ure ") re+-ine! (-.s+er) -!-$+-+i"n. #*-in5
PrP4res b-n! $-++erns !" n"+ reVec+ +ese )e-+ures.
Figure 4. (".$"si+e $ublise! eG$eri.en+-l !-+- )"r +r-ns.issi"n ") s(JI
u.-n br-in +" !i;eren+ s$ecies in seAuen+i-l $-ss-*es. 0uine- $i* (0P)5
-.s+er (@-)5 .urine ('")5 -n! r-+ s(JI $l"+s c"n+-in "ri*in-l !-+- )r". +e
<rs+ seri-l +r-ns.issi"n ...
# l"6 le&el ") 123 -*en+ nucleic -ci! .u+-+i"n5 6i+ re+en+i"n ") "nly )e6
selec+e! &-ri-n+s see.s ."s+ $l-usible5 c"nce$+s <rs+ in+r"!uce! 6i+ +e
se.in-l +r-ns.issi"n eG$eri.en+s ") P-++is"n5 Iic7ins"n -n! Li.berlin in
scr-$ie5 -n! +e re-li:-+i"n +-+ +ese -*en+s -&e -n Cin!e$en!en+ *en".eD
(re&ie6e! in re)s.
225 37
5 -n!
67
). (l"nin* ") - sin*le .u+-n+ -*en+ by eG+re.e
en!4$"in+ !ilu+i"n 6-s necess-ry +" "b+-in - $ure -*en+ s+r-in 6i+ ne*li*ible
re&ersi"n. 2uc -n in&-ri-n+ -*en+ is eGe.$li<e! by +e cl"ne! 263L -.s+er
scr-$ie -*en+ +-+ bec-.e -&irulen+ )"r .ice. 1ere -re -ls" scr-$ie s+r-ins
+-+ s"6 ."re )reAuen+ c-n*e. =n+eres+in*ly5 "ne scr-$ie s+r-in 6i+
.-r7e!ly -l+ere! +r-ns.issi"n $r"$er+ies -s recen+ly been selec+e! in .ice
by ."!i)yin* +e *lyc"syl-+i"n ") PrP5
67
- <n!in* c"nsis+en+ 6i+ -*en+
$-r+icles +i*+ly b"un! +"5 -n! inVuence! by "s+ rece$+"r PrP. 2uc bin!in*
c-n -ls" in!uce -!!i+i"n-l "s+ $r"cesses in&"l&e! in -*en+ selec+i"n. 9ile
+e -u+"rs ") +is $-$er y$"+esi:e .ul+i$le .is)"l!e! )"r.s "r
CAu-sis$eciesD ") in)ec+i"us PrP5 +e res"lu+i"n ") +ese !i;eren+ PrP )"r.s
-s n"+ been e&i!en+. 1is ne6 scr-$ie !-+- ins+e-! -r*ues ."s+
$-rsi."ni"usly )"r - .u+-ble -*en+ *en".e. Hur+er."re5 +e l"n*4
es+-blise! re&ersible s6i+cin* be+6een +e 79# -n! 139# scr-$ie -*en+
$en"+y$es
67
su**es+s +-+ .in"r -*en+ nucleic -ci! &-ri-n+s c-n $ersis+5
6i+ e-c &-ri-n+ c".in* +" +e )"re in i+s ."re )-&"r-ble en&ir"n.en+ "r
s$ecies. =n su.5 +ere is b"+ selec+i&e s+-bili+y -n! .u+-bili+y ") 123 -*en+s
+-+ .irr"rs &ir-l be-&i"r -n! +e +r-ns)er ") s+r-in4s$eci<c in)"r.-+i"n
enc"!e! by nucleic -ci!. Enli7e 6i+ nucleic -ci!s5 n" ."lecul-r ."!el eGis+s
+" su$$"r+ - c".$-r-ble $r"+ein4b-se! Cin)"r.-+i"nD +r-ns)er. '"re"&er5 +e
.ul+i$le c"n)"r.ers ") PrP res +-+ -re $resu.e! +" enc"!e -ll +e !i;eren+
scr-$ie -n! (JI -*en+ s+r-ins $r"$-*-+e! in 6+ .ice re.-in y$"+e+ic-l. >"r
-s -ny s$eci<c "r c"nsis+en+ .is)"l!in* been i!en+i<e! +-+ *ener-lly
!e<nes +e in)ec+i"us )"r. ") PrP. 1e .ul+i$le !esi*n-+i"ns )"r -ll ") +e
!i;eren+ c-$-bili+ies ") $r"$"se! PrP c"n)"r.ers c-n be .in!4b"**lin*5 e.*.5
+e PrP4res )"r.s +-+ .us+ enc"!e .-F"r s+r-in cl-sses suc -s PrP
cF!
5 PrP
sc
5
PrP
c6!
5 PrP
823
5 +e PrP4! )"r +e !ise-se )"r.5 - 1PrP )"r +e neur"+"Gic )"r.5
-n! ."s+ recen+ly5 - sub$"$ul-+i"n ") -n in)ec+i"us $r"+e-se sensi+i&e PrP4
sens )"r. (re&ie6e! in re).
31
). Per-$s +e c-$-ci+ies ") PrP -re "&ers+-+e!X
0" +":
The &tructure of Infectious Particles
9ere-s PrP4res <brils -n! -.yl"i! -**re*-+es !is+ribu+e "&er - u*e si:e
s$ec+ru.5 123 in)ec+i"us -*en+s -&e - "."*ene"us 1202 si:e -n! be-&e
-s &ir-l $-r+icles +-+ se$-r-+e )r". !is-**re*-+e! PrP.
37
=n)ec+i"us
$re$-r-+i"ns -ls" c"n+-in ul+r-s+ruc+ur-l 25 n. elec+r"n !ense $-r+icles +-+
!" n"+ bin! PrP -n+ib"!ies5 unli7e PrP -.yl"i! <brils.
11
(ells in)ec+e! 6i+ 22,
scr-$ie "r HE4(JI -*en+s -ls" $r"!uce in+r-cellul-r -rr-ys ") c".$-r-ble 25
n. &irus4li7e $-r+icles +-+ -re n"+ seen in unin)ec+e! c"n+r"ls5 eG+en!in* +e
re-li+y ") +ese $-r+icles <rs+ !escribe! .-ny ye-rs -*" in scr-$ie br-ins.
45

'"re"&er5 6en is"l-+e! in)ec+i"us $-r+icles -re !isru$+e!5 +ey rele-se
nucleic -ci!s -n! $r"+ec+i&e nucleic -ci! bin!in* $r"+eins5 -n! si.ul+-ne"usly
l"se 3 l"*s ") in)ec+i&i+y (re&ie6e! in re)s.
11
-n!
37
). 1is -!!i+i"n-l e&i!ence
$"in+s +" - $r"+ec+e! nucleic -ci! *en".e r-+er +-n +e PrP4res +-+ 6-s
n"+ !isru$+e! by +is +re-+.en+. 0i&en suc <n!in*s5 -n! +e irre)u+-ble
e&i!ence )"r .u+-ble 123 s+r-ins5 i+ is re.-r7-ble +-+ +ere -s been s" li++le
su$$"r+ )"r "r in+eres+ in $ursuin* $uri<c-+i"n ") nucleic -ci!s )r". in)ec+i"us
$-r+icles. #ll ") +e .-ny in)ec+i"us $re$-r-+i"ns 6e -&e +es+e!5 inclu!in*
s+-n!-r! PrP4res <brils .-!e +" see! +es+4+ube -.yl"i! c"n&ersi"ns5
17
-&e
yiel!e! nucleic -ci!s ") R500 n+5 ye+ n" .-F"r 123 l-b in +e $-s+ 15 y see.s
+" -&e +es+e! -ny ") +eir in)ec+i"us +issue !eri&e! see! "r c"4)-c+"r .-+eri-l
in Au-n+i+ies suBcien+ +" !e+ec+ -n -*en+ nucleic -ci! by +e insensi+i&e *el
s+-inin* .e+"!s use!.
21
1ese -n-lyses -ls" +y$ic-lly eGclu!e ."lecules ")
R200 n+. >"r -&e $re$-r-+i"ns been +es+e! by -ny s$eci<c ."lecul-r
.e+"! suc -s P(M5 +" !e+ec+ cy+"$l-s.ic nucleic -ci!s suc -s re+r"&ir-l
seAuences -n! $r"+ec+e! .i+"c"n!ri-l I># re*i"ns 7n"6n +" c"4$uri)y 6i+
in)ec+i&i+y.
21
1us +e c".."n belie) +-+ 123 -*en+s c"n+-in n" nucleic -ci!
-$$e-rs +" be b-se! "n +e $ri"n ."!el5 r-+er +-n "n !irec+ eG-.in-+i"n ")
i*ly in)ec+i"us subcellul-r $re$-r-+i"ns. 8ec-use nei+er -n in)ec+i"us )"r.
") PrP5 n"r - c-us-+i&e -*en+4s$eci<c nucleic -ci! seAuence -s ye+ been
!e<ne!5 +e n-+ure ") +e in)ec+i"us $-r+icle re.-ins un7n"6n.
0" +":
Nucleic Acids in Infectious Preparations
1ere -&e been li.i+e! -++e.$+s +" !e<ne - nucleic -ci! +-+ is essen+i-l )"r
in)ec+i"n. Kne 123 *r"u$ re$"r+e! +-+ s.-ll M>#s eG+r-c+e! )r". s+-n!-r!
263L -.s+er PrP4res scr-$ie br-in $re$-r-+i"ns 6-s -ble +" in)ec+ -ni.-ls
6en !eli&ere! 6i+ ("r $r"+ec+e! by) recPrP.
68
1is resul+ !eser&es )"ll"64u$5
!es$i+e +e !is.issi&e -$$en!e! c"..en+s -b"u+ +is in+eres+in*
c"n+ribu+i"n by +6" !".in-n+ $ri"n $r"$"nen+s.
68
#l+"u* "ur .-F"r
e.$-sis -s been +e +r-ns.issi"n -n! c-r-c+eri:-+i"n ") u.-n 123
s+r-ins5 6e -&e -ls" l""7e! -+ $"+en+i-l -*en+4s$eci<c nucleic -ci!s5
inclu!in* circul-r I>#s +-+ c"4$uri)y 6i+ in)ec+i"us 25 n. $-r+icles. 1e
rel-+i&e s+-bili+y ") 123 -*en+s5 -n! bi"l"*ic-l $r"$ensi+ies suc -s +u."r
)"r.-+i"n5 su**es+e! - cy+"$l-s.ic circul-r I># ") 14 7b5
21
r-+er +-n -n
M># &irus li7e e$-+i+is ( +-+ is uns+-ble5 -n! r-$i!ly $r"!uces .illi"ns ")
.u+-+e! -n! $en"+y$ic-lly !is+inc+ Au-sis$ecies.
Mecen+ -n-lyses ") $-r+icle nucleic -ci!s eG+r-c+e! )r". in)ec+i"us cy+"$l-s.
-&e been )-cili+-+e! by +e !e&el"$.en+ ") ne6 si.$li<e! s+-ble 123 cul+ure
."!els5 r-$i! in)ec+i&i+y -ss-ys )"r i.$r"&e! is"l-+i"n ") in)ec+i"us $-r+icles5
-n! -$$lic-+i"n ") )-i+)ul Pi 29 $"ly.er-se -.$li<c-+i"ns.
21
1e r"bus+ness
-n! <!eli+y ") +is l-s+ -$$r"-c 6-s &-li!-+e!5 bec-use nucle-se $r"+ec+e!
)ull4len*+ circul-r .i+"c"n!ri-l I>#s (.+I>#) ") 16 7b 6ere re+rie&e! )r".
in)ec+i"us cy+"$l-s.ic )r-c+i"ns. '+I># -&e been )"un! by P(M in e&ery
in)ec+i"us $re$-r-+i"n eG-.ine!5 inclu!in* s+-n!-r! br-in !eri&e! PrP4res
<brils use! +" see! +es+4+ube PrP c"n&ersi"ns. =+ is li7ely +-+ -ll cy+"$l-s.ic
+issue eG+r-c+s use! +" ini+i-+e PrP4res 6ill -ls" s"6 .+I># by P(M5 -s 6ell
-s r"!en+ re+r"&ir-l seAuences. 9ile +ese -re unli7ely +" !e<ne "r enc"!e
123 -*en+ s+r-ins5 +ey $r"&i!e - *""! $"si+i&e c"n+r"l )"r eBcien+ nucleic
-ci! eG+r-c+i"n.
0" +":
$ircular &phin8 "NAs4 #nsuspected %8changes with
the *etagenomeN
Esin* .ul+i$le !is$l-ce.en+ -.$li<c-+i"n ('I#) s+r-+e*ies5 se&er-l n"&el
circul-r C2$inGD I># ele.en+s5 c".$-+ible 6i+ +e $re!ic+e! 123 &ir-l si:e5
-&e n"6 been is"l-+e! )r". in)ec+i"us $-r+icles $r"$-*-+e! in -.s+er br-in
(6i+ 263L scr-$ie) -n! .urine 011 cells (6i+ HE4(JI). Enli7e .+I>#
seAuences +-+ 6ere s$ecies s$eci<c -n! -bun!-n+5 +e is"l-+e! 2$inG
seAuences 6ere $resen+ -+ +e l"6 le&els eG$ec+e! )"r - 123 -*en+ in sucr"se
*r-!ien+ $uri<e! $-r+icles. 1ey 6ere "."l"*"us by P(M re*-r!less ")
s$ecies "r -*en+ s+r-in. 1ese +6" I>#s 6ere n"+ !e+ec+-ble in -ny ") +e
en:y.es5 ce.ic-ls5 "r s"lu+i"ns use!5 &eri)yin* +eir "ri*in in +e $-r+icle
$re$-r-+i"ns. 8ec-use +e KMHs in +ese +6" 2$inG ele.en+s 6ere -ls"
$resen+ by P(M5 -lbei+ -+ - .uc l"6er le&el5 in unin)ec+e! $-r-llel
$re$-r-+i"ns5 +eir r"le in 123 in)ec+i"n is in!e+er.in-+e. @"6e&er5 +eir r"le
c-n be e&-lu-+e! usin* -n+isense s+r-+e*ies. =+ .-y -ls" be in)"r.-+i&e +"
eG-.ine $"+en+i-l .u+-+i"ns in +e unin)ec+e! "."l"*s. =n in)ec+i"us
$-r+icle $re$-r-+i"ns5 - )e6 -!!i+i"n-l $r"+ec+e! circul-r I>#s -&e -ls" been
i!en+i<e!5 -n! +ese !eser&e )ur+er s+u!y *i&en +e in!e$en!en+ s+r-in5
re$lic-+i"n !yn-.ics5 -n! en&ir"n.en+-l "ri*in ") 123s. 1ese +y$es ")
seAuences -l+ern-+i&ely c"ul! be in&"l&e! in +e recrui+.en+ ") n"n4in)ec+i"us
-.yl"i!s5 n"+ "nly in 123s5 bu+ in "+er neur"!e*ener-+i&e !ise-ses.
Me.-r7-bly5 b"+ +e circul-r 1.8 7b -n! - 2.4 7b 2$inG ele.en+s c"n+-in
"$en re-!in* )r-.e (KMH) "."l"*ies 6i+ $"r+i"ns ") +e l-r*e circul-r P12
7b $l-s.i!s ") #cine+"b-c+er5 bu+ +e $-ren+ b-c+eriu. 6-s n"+ -$$-ren+ in
+e in)ec+i"us eG+r-c+s. 1ese +6" 2$inG ele.en+s -ls" c"n+-in n"n4c"!in*
in+er&enin* seAuences +-+ -re n"+ in +e !-+-b-se5 i.$lic-+in* -n
e&"lu+i"n-ry !i;erence )r". +e s+-n!-r! b-c+eri-l $l-s.i!s. #cine+"b-c+er
-re 6i!es$re-! in +e en&ir"n.en+5 inclu!in* s"il -n! 6-+er5 -re -n+ibi"+ic4
resis+-n+5 -n! -re c"..ens-l in)ec+i"ns +-+ -re n"+ +y$ic-lly $-+"*enic.
1us +ey r-ise +6" )un!-.en+-lly ne6 c"nce$+s. Hirs+5 +-+ l"6 $-+"*enici+y
en&ir"n.en+-l I>#s .-y resi!e in - Auiescen+ "r l-+en+ )"r. in .-..-ls
un+il +e "r*-nis. is s+resse!. 2ec"n!5 2$inG ele.en+s .-y re$resen+ +e
+i$ ") +e iceber* ") uneG$ec+e! .e+-*en".ic eGc-n*es 6i+ .-..-ls: -
r-+er eGci+in* ne6 !irec+i"n 6i+ br"-! r-.i<c-+i"ns.
0" +":
&ummary
1e s+ruc+ure -n! s+r-in4!e+er.inin* ."lecul-r c".$"nen+s ") in)ec+i"us 123
$-r+icles re.-ins un7n"6n. #n en"r."us &-rie+y ") e&i!ence c"n+r-!ic+s +e
c"nclusi"n +-+ 123 in)ec+i"us -*en+s -re .-!e ") "s+ PrP 6i+"u+ nucleic
-ci! "r -n en&ir"n.en+-l c".$"nen+. Hirs+5 !i;eren+ -*en+ s+r-ins *i&e +e
s-.e PrP4res $-++ern5 -n! c"n&ersely5 s-.$les 6i+ &ery !i;eren+ PrP4res
$-++erns c-n $r"$-*-+e +e i!en+ic-l in)ec+i"us -*en+. 1us "bser&e! PrP
c"n)"r.ers !" n"+ enc"!e "r $re!ic+ s+r-ins. 2ec"n!5 -ll )"r.s ") !e+ec+-ble
PrP c-n be !es+r"ye! 6i+ n" l"ss ") in)ec+i&i+y. PrP -s -ls" been
un!e+ec+-ble in cells 6i+ i* in)ec+i"us +i+ers. 1ir!5 +e "s+ rec"*ni:es
-n! ."un+s e-rly inn-+e i..une !e)enses -*-ins+ in!i&i!u-l 123 -*en+s -n!
+is !e+er.ines l-+ency -n! incub-+i"n +i.e. H"ur+5 PrP4res -.yl"i! -$$e-rs
-s $-r+ ") - l-+e !e)ense .ec-nis. -*-ins+ - )"rei*n -*en+5 -n! 123 -*en+
re$lic-+i"n !e."ns+r-+es - &-s+ly !i;eren+ +r-Fec+"ry +-n +e c"n&ersi"n
7ine+ics ") PrP4res (+e Cin)ec+i"usD )"r.). Hi)+5 PrP -c+s -s - reAuire! "s+
rece$+"r )"r -*en+ sur&i&-l. =n +is c-$-ci+y i+ c-n $r"+ec+ +e -*en+ 6ile
-ll"6in* +e "s+ +" sur&i&e )"r ye-rs. 2iG+5 -s "+er 0P= $r"+eins5 PrP
)-cili+-+es cell4+"4cell +r-ns)er5 -n! c-n be use! by se&er-l in)ec+i"us -*en+s5
n"+ Fus+ 123s. 2e&en+5 -s in 123 in)ec+i"ns5 "+er &iruses c-n in!uce
.is)"l!e! $r"+ein C$ri"nD -**re*-+es -s $-r+ ") -n -n+i&ir-l inn-+e i..une
res$"nse. 3i*+5 +e -bili+y +" )"l! in+" -n -.yl"i! s+-+e is - $r"$er+y s-re!
by .-ny $r"+eins -n! $e$+i!es.
#.yl"i! -**re*-+i"n is - $r"cess +-+ is i*ly c"nser&e! in e&"lu+i"n -n! i+
!"es n"+ reAuire in)ec+i"n. =n ye-s+5 suc c"n&ersi"ns -re in&"l&e! in - 6i!e
r-n*e ") )unc+i"ns5 inclu!in* +r-nscri$+i"n-l -n! +r-nsl-+i"n-l re*ul-+i"n.
38

Iense resis+-n+ b-c+eri-l bi"<l.s )unc+i"n in s"ci-li:-+i"n -n! $r"+ec+i"n
69

-n! c-n be c"nsi!ere! +"*e+er 6i+ .-..-li-n -.yl"i!s5 inclu!in* PrP -n!
#I $l-Aues +-+ c"n+-in .-ny "+er ele.en+s.
23
=n)ec+i"n $"ses -!!i+i"n-l
uneG$l"re! "$$"r+uni+ies. 1e !isc"&ery ") b-c+eri-l $l-s.i!4li7e ele.en+s
-ss"ci-+e! 6i+ 123 in)ec+i"us $-r+icles r-ises +e issue ") unsus$ec+e!
eGc-n*es be+6een .-..-ls -n! b-c+eri-l &ir-l ele.en+s in !ise-se. 2".e
") +ese &ir-l ele.en+s .-y be +e r""+ c-use ") 123s -s 6ell -s - !i&ersi+y ")
cr"nic c"n!i+i"ns. #l+ern-+i&ely5 suc ele.en+s .-y $r"."+e +e
-**re*-+i"n ") <brill-r $r"+eins in neur"!e*ener-+i"ns ") un7n"6n e+i"l"*y.
'e+-*en".ic ele.en+s5 -l"n* 6i+ en&ir"n.en+-l +"Gins5 surely !eser&e
br"-!er -++en+i"n -s c-us-l )-c+"rs in #I -n! "+er l-+e4"nse+ !ise-ses.
0" +":
Acknowledgments
1is 6"r7 6-s su$$"r+e! by >=@ *r-n+ >=>I2 *r-n+ M01 012674
0" +":
"isclosure of Potential $onflicts of Interest
>" $"+en+i-l c"nVic+s ") in+eres+ 6ere !iscl"se!.
0" +":
3ootnotes
Pre&i"usly $ublise! "nline:
666.l-n!esbi"science.c".%F"urn-ls%&irulence%-r+icle%24838
0" +":
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43. 2c6-r+: L5 8"les 8M. 'icr"bi-l -.yl"i!s 4 )unc+i"ns -n! in+er-c+i"ns
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10.1016%F..ib.2012.12.001. YP'( )ree -r+icleZ YPub'e! Z Y(r"ss Me)Z
44. 1ellun* 25 Hl"ri" 15 Vill- V5 ("rs-r" #5 #ren- 25 #.ic" (5 e+ -l. #$"$+"+ic
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-c+i&i+y in r-+ cerebell-r *r-nule cells +re-+e! 6i+ +e $ri"n $r"+ein )r-*.en+
1064126. >eur"bi"l Iis. 2000;7:299309. !"i: 10.1006%nb!i.2000.0301.
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46. `"u '5 K++enber* 05 2)err-::- 0H5 ,-s._:-s (=. @i*ly neur"+"Gic
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48. Li+-."+" 15 'ur-."+" 15 '"ri 25 I"4Er- L5 1-+eisi J. #bn"r.-l is")"r.
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49. Llein '#5 Hri** M5 Hlecsi* 35 M-eber #J5 L-lin7e E5 8lue+.-nn @5 e+ -l. #
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50. '-nueli!is ,5 `-i+se& =5 L"ni P5 ,u `4W5 Hl-&ell M#5 Hri+c 9. H"llicul-r
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55. >isi!- >5 L-+-.ine 25 '-nueli!is ,. Meci$r"c-l in+er)erence be+6een
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67. (-ncell"++i 35 '--l 2P5 2".er&ille M5 Ii-c7 #5 8r"6n I5 Picc-r!" P5 e+ -l.
P"s+4+r-nsl-+i"n-l c-n*es +" PrP -l+er +r-ns.issible s$"n*i)"r.
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!e$en!en+ "u+er .e.br-ne eGc-n*e in .yG"b-c+eri-: *ene+ic !e+er.in-n+s
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70. '-nueli!is 335 Li. J5 #n*el" J>5 '-nueli!is ,. 2eri-l $r"$-*-+i"n ")
(reu+:)el!+4J-7"b !ise-se in *uine- $i*s. Pr"c >-+l #c-! 2ci E 2 #.
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71. '-nueli!is 335 0"r*-c: 3J5 '-nueli!is ,. =n+ers$ecies +r-ns.issi"n ")
(reu+:)el!+4J-7"b !ise-se +" 2yri-n -.s+ers 6i+ re)erence +" clinic-l
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Jurnal O
Pri"n. 2012 #$ril 1; 6(2): 108115.
!"i: 10.4161%$ri.18666
P'(=I: P'(3366352
'"lecul-r $-+"*enesis ") s$"r-!ic $ri"n !ise-ses in .-n
Jiri 0. 2-)-rd
#u+"r in)"r.-+i"n / ("$yri*+ -n! ,icense in)"r.-+i"n /
0" +":
#bs+r-c+
1e ye-s+5 )un*-l -n! .-..-li-n $ri"ns !e+er.ine eri+-ble -n! in)ec+i"us
+r-i+s +-+ -re enc"!e! in -l+ern-+i&e c"n)"r.-+i"ns ") $r"+eins. 1ey c-use
le+-l s$"r-!ic5 )-.ili-l -n! in)ec+i"us neur"!e*ener-+i&e c"n!i+i"ns in .-n5
inclu!in* (reu+:)el!+4J-7"b !ise-se ((JI)5 0ers+.-nn42+r]ussler42cein7er
syn!r".e (022)5 7uru5 s$"r-!ic )-+-l ins".ni- (2H=) -n! li7ely &-ri-ble
$r"+e-se4sensi+i&e $ri"n"$-+y (VP2Pr). 1e ."s+ $re&-len+ ") u.-n $ri"n
!ise-ses is s$"r-!ic (s)(JI. Mecen+ -!&-nces in -.$li<c-+i"n -n! !e+ec+i"n ")
$ri"ns le! +" c"nsi!er-ble "$+i.is. +-+ e-rly -n! $"ssibly $reclinic-l
!i-*n"sis -n! +er-$y .i*+ bec".e - re-li+y. #l+"u* se&er-l !ru*s -&e
-lre-!y been +es+e! in s.-ll nu.bers ") s(JI $-+ien+s5 +ere is n" cle-r
e&i!ence ") -ny -*en+Os eBc-cy. 1ere)"re5 i+ re.-ins cruci-l +" !e+er.ine
+e )ull s$ec+ru. ") s(JI $ri"n s+r-ins -n! +e c"n)"r.-+i"n-l )e-+ures in +e
$-+"*enic u.-n $ri"n $r"+ein *"&ernin* re$lic-+i"n ") s(JI $ri"ns.
Mese-rc in +is !irec+i"n is essen+i-l )"r +e r-+i"n-l !e&el"$.en+ ")
!i-*n"s+ic -s 6ell -s +er-$eu+ic s+r-+e*ies. '"re"&er5 +ere is *r"6in*
rec"*ni+i"n +-+ )un!-.en+-l $r"cesses in&"l&e! in u.-n $ri"n $r"$-*-+i"n
in+ercellul-r in!uc+i"n ") $r"+ein .is)"l!in* -n! see!e! -**re*-+i"n ")
.is)"l!e! "s+ $r"+eins -re ") )-r 6i!er si*ni<c-nce. 1is insi*+ le-!s +"
ne6 -&enues ") rese-rc in +e e&er46i!enin* s$ec+ru. ") -*e4rel-+e!
u.-n neur"!e*ener-+i&e !ise-ses +-+ -re c-use! by $r"+ein .is)"l!in*
-n! +-+ $"se - .-F"r c-llen*e )"r e-l+c-re.
Ley6"r!s: c"n)"r.-+i"n ") u.-n $ri"n $r"+ein5 !i-*n"sis5 u.-n $ri"n
s+r-ins5 neur"!e*ener-+i"n5 neur"$-+"l"*ic cl-ssi<c-+i"n5 s$"r-!ic
(reu+:)el!+4J-7"b !ise-se (s(JI)
0" +":
=n+r"!uc+i"n
Pri"n !ise-ses51 "ri*in-lly c-lle! +r-ns.issible s$"n*i)"r.
ence$-l"$-+ies52 -re in&-ri-bly )-+-l neur"!e*ener-+i&e !ise-ses +-+
-;ec+ u.-ns -n! -ni.-ls. 1e 7ey c-r-c+eris+ics ") u.-n s$"n*i)"r.
ence$-l"$-+ies -re (1) e+er"*enei+y ") +e clinic-l -n! $-+"l"*ic
$en"+y$e5345 (2) - sin*le $-+"l"*ic $r"cess5 6ic .-y $resen+ -s -
s$"r-!ic5 *ene+ic5 "r in)ec+i"us illness56 -n! (3) +e -*e !e$en!ence ")
*ene+ic -s 6ell -s s$"r-!ic )"r.s: +e -nnu-l $e-7 inci!ence is 36 c-ses $er
.illi"n $e"$le be+6een 65 -n! 79 ye-rs ") -*e.657 Ies$i+e +eir r-ri+y5
u.-n $ri"n !ise-ses -&e *-ine! c"nsi!er-ble i.$"r+-nce bec-use +eir
uniAue e+i"l"*y -n! $-+"*enesis c-llen*e! b-sic $rinci$les ") bi"l"*y.
Hur+er."re5 $ri"n !ise-ses c-n be +r-ns.i++e! be+6een u.-ns -s 6ell -s
)r". -ni.-ls +" u.-ns by -n -*en+ +-+ is i*ly resis+-n+ +" in-c+i&-+i"n
-n! 6ic +us $"ses n"&el $r"ble.s +" !ise-se c"n+r"l -n! $ublic e-l+.
Hin-lly5 bec-use ") +e .-r7e! e+er"*enei+y ") +eir clinic-l $en"+y$e5
$ri"n !ise-ses -re !iBcul+ +" !i;eren+i-+e )r". "+er -*e4rel-+e! br-in
neur"!e*ener-+i"ns5 - )e-+ure +-+ -s $r".$+e! +e es+-blis.en+ ")
s$eci-li:e! $ri"n !ise-se sur&eill-nce cen+ers 6"rl!6i!e. @u.-n $ri"n
!ise-ses -ls" inclu!e ineri+e! )"r.s -s 6ell -s )"r.s -cAuire! by in)ec+i"n
(1-ble 1). @"6e&er5 +is re&ie6 )"cuses "n +e ."lecul-r -s$ec+s ") +e
$-+"*enesis ") s$"r-!ic )"r.s.
1-ble +u.bn-il
1-ble 1. 3+i"l"*ic cl-ssi<c-+i"n ") u.-n $ri"n !ise-ses
0" +":
Hr". sl"6 &irus +" +e $ri"n c"nce$+
2$"r-!ic (reu+:)el!+4J-7"b !ise-se (s(JI) is +e ."s+ c".."n )"r. ") u.-n
s$"n*i)"r. ence$-l"$-+y5 -cc"un+in* )"r P85Q ") -ll u.-n $ri"n
!ise-se.8 1e +er. C(reu+:)el!+4J-7"b !ise-seD ((JI) 6-s in+r"!uce! by
#l)"ns '-ri- J-7"b in 19215 6" re)erre! +" - $re&i"us c-se !escribe! by
@-ns 0er-r! (reu+:)el!+ in 1920.9510 1ese "ri*in-l c-ses 6ere clinic-lly
e+er"*ene"us5 -n! neur"$-+"l"*ic re&ie6 ") +e is+"ric-l .-+eri-l 6i+
."!ern +""ls $r"&i!e! c"n<r.-+i"n ") +e !i-*n"sis ") (JI in "nly +6" ") +e
"ri*in-l <&e c-ses.11 K&er +e neG+ +6" !ec-!es5 +e clinic"$-+"l"*ic-l
cl-ssi<c-+i"n ") (JI re.-ine! uncer+-in -n! )"r eG-.$le 9ils"n c"nclu!e!
+-+ (JI is - C!u.$in* *r"un! )"r se&er-l r-re c-ses ") $resenile
!e.en+i-D12. #l+"u* ."n"*r-$ by Lirscb-u.13 lis+e! +e clinic-l -n!
$-+"l"*ic c-r-c+eris+ics ") 150 c-ses !i-*n"se! be)"re 19655 i+ inclu!e!
-ls" c-ses suc -s (reu+:)el!+Os "ri*in-l c-se5 6ic 6"ul! n"+ )ul<ll cri+eri-
)"r +e !i-*n"sis ") (JI +"!-y. =.$"r+-n+ly5 in +e 1960s5 >e&in -n! J"nes
!escribe! +e +y$ic-l clinic-l sy.$+".s5 elec+r"ence$-l"*r-. (330)5 -n!
neur"$-+"l"*ic c-n*es5 inclu!in* s$"n*i)"r. c-n*e5 6ic +"*e+er -re
n"6 rec"*ni:e! -s +e $-r-!i*. )e-+ures ") s$"r-!ic (JI.14 2ubseAuen+ly5
ne6 s$"r-!ic )"r.s ") +e s$"n*i)"r. ence$-l"$-+ies 6i+ uniAue
$en"+y$ic )e-+ures 6ere !escribe!; s$eci<c-lly5 s$"r-!ic )-+-l ins".ni- (2H=)
in 1997515516 -n! +e l-+es+ li7ely ne6 c-n!i!-+e5 &-ri-ble $r"+e-se4sensi+i&e
$ri"n"$-+y (VP2Pr) in 2008.17
("n+r"&ersy c"ncernin* +e c-use ") u.-n s$"n*i)"r. ence$-l"$-+ies
-s $"l-ri:e! +e scien+i<c c"..uni+y )"r !ec-!es. 1e 1950s s-6
c"nsi!er-ble in+eres+ in -n e$i!e.ic ") - neur"!e*ener-+i&e !ise-se5 7uru5
c-r-c+eri:e! $rinci$-lly by - $r"*ressi&e cerebell-r -+-Gi-5 -."n* +e H"re
$e"$le ") +e 3-s+ern @i*l-n!s ") P-$u- >e6 0uine-.18519 Hiel!6"r7 by
(-rle+"n 0-F!use7 -n! Vincen+ ì*-s su**es+e! +-+ 7uru 6-s +r-ns.i++e!
!urin* c-nnib-lis+ic )e-s+s.20 =.$"r+-n+ly5 in 1959 @-!l"6 $"in+e! "u+ +e
si.il-ri+ies be+6een 7uru -n! scr-$ie ") see$ -+ +e neur"$-+"l"*ic -n!
clinic-l le&els -n! su**es+e! +-+ u.-n !ise-ses .i*+ -ls" be
+r-ns.issible.21 2ubseAuen+ +r-ns.issi"n ") 7uru (in 1966) -n! +en (JI (in
1968) by in+r-cerebr-l in"cul-+i"n ") br-in "."*en-+es in+" ci.$-n:ees5
6"r7 6ic 6-s c"n!uc+e! by 0-F!use75 0ibbs5 -n! c"lle-*ues5 6-s -
l-n!.-r7 !isc"&ery 6ic le! +" +e c"nce$+ ") +e C+r-ns.issible s$"n*i)"r.
ence$-l"$-+iesD22523. 1e +r-ns.issi"n ") 0ers+.-nn42+r]ussler42cein7er
!ise-se (022) )"ll"6e! in 198124 -n! )-+-l )-.ili-l ins".ni- (HH=) in 1995.25
=n+eres+in*ly5 J-7"b5 sus$ec+in* in is "ri*in-l "bser&-+i"ns +-+ +e c"n!i+i"n
.i*+ be +r-ns.issible5 in"cul-+e! r-bbi+s eG$eri.en+-lly5 in -n -++e.$+ +"
!e."ns+r-+e +is in +e 1920s.26 @"6e&er5 +-n7s +" +e i.$"r+-n+ r"le ")
seren!i$i+y in science5 is eG$eri.en+ 6-s unsuccess)ul -n! 6e 7n"6 n"6
+-+ r-bbi+s -re uniAuely resis+-n+ +" $ri"n in)ec+i"ns.27
1e +r-ns.issi"n ") (JI -n! ") 7uru -ll"6e! re<ne.en+ ") +e !i-*n"s+ic
$-+"l"*ic cri+eri- )"r u.-n s$"n*i)"r. ence$-l"$-+y -n! le! +" +e
c"nclusi"n +-+ -ll +e u.-n c"n!i+i"ns s-re c".."n is+"$-+"l"*ic
)e-+ures: s$"n*i)"r. &-cu"l-+i"n (-;ec+in* -ny $-r+ ") +e cerebr-l *r-y
.-++er)5 neur"n-l l"ss5 -n! -s+r"cy+ic $r"li)er-+i"n +-+ .-y be -cc".$-nie!
by -.yl"i! $l-Aues.28431 Kn -n-l"*y 6i+ scr-$ie in see$5 i+ 6-s -ssu.e!
+-+ +e c-us-+i&e -*en+ .us+ be s".e +y$e ") -+y$ic-l Csl"6 &irus5D +e +er.
2i*ur!ss"n c"ine! in 1954 )"r scr-$ie in)ec+i"n.2532 Me*re++-bly5 !es$i+e
eG+ensi&e e;"r+s in 3ur"$e -n! +e E25 n" n"n4"s+ I># "r M># c"ul! be
)"un!5 -n! - *r"6in* b"!y ") !-+- $"in+e! +" - c-us-+i&e -*en+ -&in*
uniAue c-r-c+eris+ics.33534 '"s+ rese-rcers +"!-y -cce$+ +e ."!el
-cc"r!in* +" 6ic +e in)ec+i"us $-+"*en res$"nsible )"r u.-n $ri"n
!ise-ses is -n -bn"r.-l $r"+ein5 !esi*n-+e! PrP2c 1.
1e !isc"&ery +-+ $r"+eins c"ul! be in)ec+i"us re$resen+e! - ne6 $-r-!i*.
") ."lecul-r bi"l"*y -n! .e!icine. #l+"u* "ri*in-lly !ee.e! ere+ic-l5 +is
$r"+ein4"nly ."!el is n"6 su$$"r+e! by - 6e-l+ ") bi"ce.ic-l5 *ene+ic -n!
-ni.-l s+u!ies.6535438 '"re"&er5 +e c"nce$+ ") $ri"n !ise-ses -s
i.$"r+-n+ i.$lic-+i"ns )"r "+er neur"!e*ener-+i&e !is"r!ers. Mecen+ s+u!ies
6i+ #.yl"i! J5 +-u5 a4synuclein5 un+in*+in5 -n! su$er"Gi!e !is.u+-se 1
su**es+ +-+ ."lecul-r -n! cellul-r .ec-ni.s +-+ 6ere <rs+ !isc"&ere! in
s+u!ies ") $ri"ns -re in&"l&e! in +e $-+"*enesis ") "+er neur"!e*ener-+i&e
!is"r!ers -ss"ci-+e! 6i+ +e -ccu.ul-+i"n ") .is)"l!e! $r"+eins5 inclu!in*
P-r7ins"nis.5 @un+in*+"n !ise-se5 -.y"+r"$ic l-+er-l scler"sis (#,2)5 -n!
#l:ei.er !ise-se.39443
0" +":
P-+"*ene+ic .ec-nis.s ") u.-n s$"r-!ic $ri"n !ise-ses
1e b-sic e&en+ s-re! by -ll +ree )"r.s ") $ri"n !ise-ses s$"r-!ic5
ineri+e! -n! -cAuire! by in)ec+i"n is - c-n*e in c"n)"r.-+i"n ") +e
n"r.-l "r cellul-r PrP (PrP() 6ic is c"n&er+e! in+" - $-+"*enic PrP is")"r.
c".."nly i!en+i<e! -s PrP2c )"r $r"+"+y$ic scr-$ie (2c) PrP.1 @u.-n PrP( is
enc"!e! by +e PrP *ene (PM>P) "n cr"."s".e 20 -n! eG$resse! -+
!i;eren+ le&els in ."s+ .-..-li-n cells. =+ c".$rises 209 -.in" -ci!s (23
231)5 +6" si+es ") >4lin7e! *lyc"syl-+i"n5 - !isul<!e b"n! -n! - *lyc"li$i!
-nc"r.44449 1e &-ri-ble !e*ree ") *lyc"syl-+i"n is res$"nsible )"r +e
$resence ") !i45 ."n"4 -n! un4*lyc"syl-+e! )"r.s ") PrP(. 8ec-use ") +e
*lyc"li$i! -nc"r5 ."s+ ") +e PrP( is eG+r-cellul-rly lin7e! in s$eci-li:e!
c"les+er"l4ric !".-ins (c-&e"li) ") +e cell $l-s.- .e.br-ne.48550 =n
n"r.-l c"n)"r.-+i"n5 u.-n PrP( c".$rises - (4+er.in-l *l"bul-r !".-in
(in&"l&in* resi!ues 127231)5 6ic c"nsis+s ") +ree a4elices -n! +6" s"r+
J4see+s.51 =n c"n+r-s+5 +e >4+er.inus is uns+ruc+ure!.51
1e PrP2c5 in c"n+r-s+5 is $-+"*enic5 in)ec+i"us -n! !is$l-ys !i;eren+
bi"$ysic-l )e-+ures5 )"r.in* ins"luble -**re*-+es ") !i;eren+ si:es 6i+
$re!".in-n+ly J4see+ sec"n!-ry s+ruc+ure; +e (4+er.in-l re*i"n is rel-+i&ely
resis+-n+ +" $r"+e"ly+ic !e*r-!-+i"n.52454 1e c"n)"r.-+i"n-l +r-nsi+i"n +-+
un!erlies +ese $r"n"unce! c-n*es is belie&e! +" in&"l&e re)"l!in* ") +e (4
+er.in-l re*i"n 6ereby +e a4elic-l s+ruc+ures ") PrP( -re re$l-ce! by J4
see+ +" !i;eren+ eG+en+s -n! 6i+ &-ri-ble $-++erns.55 #l+"u* ins"lubili+y
-n! $r"+e-se resis+-nce 6ere +e "ri*in-l !e<nin* )e-+ures ") PrP2c5 +e
<n!in* ") $r"+e-se4sensi+i&e s.-ll "li*".ers ") $-+"*enic PrP2c 565 57
si*ni<c-n+ly br"-!ene! +e s$ec+ru. ") $-+"*enic c"n)"r.ers.
#l+"u* s".e -u+"rs belie&e +-+ +e +"Gici+y in $ri"n !ise-se c-n be
eG$l-ine! -s - l"ss ") )unc+i"n ") PrP( !ue +" +e c"n)"r.-+i"n-l
+r-ns)"r.-+i"n558 "+ers -r*ue +-+ - *-in ") +"Gic )unc+i"n is ."re
li7ely.59560 >e&er+eless5 +ere is *ener-l -*ree.en+ +-+ PrP( ser&es -s -
subs+r-+e )"r c"n&ersi"n +" PrP2c -n! -s - .-F"r rece$+"r )"r +"Gic e;ec+s ")
PrP2c. 1us +e neur"$r"+ec+i&e )unc+i"n $ysi"l"*ic-lly $r"&i!e! by PrP(
c"ul! be l"s+ )"ll"6in* i+s c"n&ersi"n +" PrP2c. 1e $re&-ilin* $resence ")
PrP2c "n neur"n-l $l-s.- .e.br-ne -ls" -+ +e syn-$se .i*+ eG$l-in +e
6i!es$re-! s$"n*i)"r. !e*ener-+i"n5 6ic c-n be &ie6e! -s in+r-cellul-r
e!e.-. #ll +ese c-n*es -re $-+"*n"."nic ") s(JI. #$"$+"sis -n!
"Gi!-+i&e s+ress -re re$"r+e! +" "ccur 6en PrP2c -**re*-+es )"r. -+ +e cell
sur)-ce -n! .-y 6ell c"n+ribu+e +" +e neur"n-l cell l"ss +-+ is $r".inen+ in
$ri"n !ise-ses ") l"n* !ur-+i"n -n! in $ri"n !ise-ses li7e 2H=5 6ic .-ni)es+
n" "r .ini.-l s$"n*i"sis -s 6ell -s se&ere neur"n-l l"ss.61 #s+r"*li"sis5 -
c".."n re-c+i"n +" inFury5 is c"nsi!ere! - sec"n!-ry res$"nse.
0" +":
1e "ri*in -n! $en"+y$ic e+er"*enei+y ") s(JI
2e&er-l eG$l-n-+i"ns -&e been $r"$"se! )"r +e e+i"l"*y ") s$"r-!ic $ri"n
!ise-ses. 1ese inclu!e s$"n+-ne"us s".-+ic .u+-+i"ns in +e PM>P *ene "r
r-re s+"c-s+ic c"n)"r.-+i"n-l c-n*es in +e s+ruc+ure ") PrP( 62. 1ese
eG$l-n-+i"ns $resu$$"se +-+ +e .u+-n+ PrP2c 6"ul! -&e +" be c-$-ble ")
recrui+in* 6il!4+y$e PrP(; "6e&er5 +is $r"cess 6ic .i*+ "ccur 6i+ s".e
.u+-+i"ns "r c"n)"r.-+i"ns bu+ is unli7ely 6i+ "+ers.63 #cc"r!in* +" -
sec"n! eG$l-n-+i"n5 l"6 -."un+s ") PrP2c4li7e is")"r.s -re n"r.-lly $resen+
in br-in5 -n! $"ssibly b"un! +" "+er $r"+eins suc -s e-+ s"c7 $r"+eins5
"6e&er5 +is $r"+ec+i&e .ec-nis. )-ils 6i+ -*in*.64565 Hin-lly5 i+ -s been
su**es+e! +-+ -+ le-s+ s".e c-ses ") -$$-ren+ s(JI resul+ )r". c"&er+5 l"64
le&el eG$"sure +" - Cc".."n eG+ern-l )-c+"rD66.
9i+ ."re c-ses in&es+i*-+e! -)+er +e "ri*in-l re$"r+s by J-7"b5 i+ bec-.e
cle-r +-+ +e clinic-l -s 6ell -s is+"$-+"l"*ic )e-+ures ") s(JI -re
re.-r7-bly !i&erse5 $er-$s .-7in* +e u.-n $ri"n !ise-ses +e ."s+
e+er"*ene"us ") -ll neur"!e*ener-+i&e !ise-se. Kn +e b-sis ") $re!".in-n+
clinic-l -n! $-+"l"*ic )e-+ures5 +e )"ll"6in* $en"+y$ic sub+y$es ") s(JI
6ere $r"$"se! in +e 1980s: 1) .y"cl"nic "r c"r+ic"4s+ri-+-l4s$in-l5 2)
-.-ur"+ic "r @ei!en-in5 3) cl-ssic-l "r !i;use5 4) +-l-.ic5 5) -+-Gic "r
cerebell-r5 -n! 6) -.y"+r"$ic.67469 Mese-rcers +"!-y *ener-lly -*ree +-+
+e *en"+y$e -+ c"!"n 129 ") +e cr"."s".-l *ene PM>P5 -n! +" s".e
!e*ree +e $en"+y$es ") +ese !ise-ses5 un!erlie susce$+ibili+y +" $ri"n
!ise-ses.5 #!!i+i"n-lly5 .-ny lines ") e&i!ence )r". eG$eri.en+s 6i+
l-b"r-+"ry $ri"n s+r-ins su$$"r+ +e &ie6 +-+ +e $en"+y$e ") s(JI?i+s
!is+inc+i&e incub-+i"n +i.e5 clinic-l )e-+ures5 -n! br-in $-+"l"*y?is
enci$ere! in +e s+r-in4s$eci<c c"n)"r.-+i"n ") PrP2c 5657073. @"6e&er5 in
c"n+r-s+ +" +e eG$eri.en+s 6i+ l-b"r-+"ry r"!en+ $ri"n s+r-ins5 in 6ic +e
!i*es+i"n ") br-in PrP2c 6i+ $r"+e"ly+ic en:y.e $r"+ein-se L (PL)
c"nsis+en+ly resul+s in - sin*le $r"+e-se4resis+-n+ !".-in 6i+ .-ss P19 7I-5
+e "u+c".e in s(JI is ."re c".$leG. Iis+inc+i&e *lyc"syl-+i"n $-++erns -n!
u$ +" )"ur PL4resis+-n+ )r-*.en+s ") +e $-+"*enic $ri"n $r"+ein (rPrP2c)
)"un! in s(JI br-ins -re e-sily !is+in*uis-ble "n 6es+ern bl"+ (98).55715744
77
1e 98 <n!in*s +"*e+er 6i+ u.-n PM>P *ene $"ly."r$is. le! P-rci5
0-.be++i5 -n! c"lle-*ues +" $"si+ - clinic"$-+"l"*ic-l cl-ssi<c-+i"n ") s(JI
in+" <&e "r siG sub+y$es; n"+-bly5 +e 98 c-r-c+eris+ics ") PrP2c bree! +rue
u$"n +r-ns.issi"n +" susce$+ible +r-ns*enic .ice -n! 0uine- $i*s ((-&i-
$"rcellus).5571574578 #n -l+ern-+i&e cl-ssi<c-+i"n ") +e PrP2c +y$es -n! +eir
$-irin* 6i+ (JI $en"+y$es -s been $r"$"se! by ("llin*e -n!
c"ll-b"r-+"rs.37575576579 1is cl-ssi<c-+i"n !i;ers )r". +e $re&i"us "ne in
+6" .-F"r -s$ec+s: <rs+5 i+ rec"*ni:es +ree (n"+ +6") PrP2c elec+r"$"re+ic
."bili+ies -n! sec"n!5 i+ -ls" i!en+i<es PrP2c is")"r.s 6i+ !i;eren+ r-+i"s ")
+e +ree PrP *lyc")"r.s.37 #l+"u* +e !ise-se $en"+y$es ") $-+ien+s 6i+
s(JI -re re.-r7-bly e+er"*ene"us5 21 7I- )r-*.en+s ") un*lyc"syl-+e!
PrP2c (1y$e 1) )reAuen+ly !i;er )r". +e !ise-se !ur-+i"n -n! $en"+y$es
-ss"ci-+e! 6i+ +e 19 7I- )r-*.en+s ") un*lyc"syl-+e! PrP2c (1y$e
2).355571574
(u.ul-+i&ely5 +ese <n!in*s -r*ue +-+ +e PrP2c +y$e re$resen+s ye+ -n
-!!i+i"n-l .-F"r ."!i<er ") +e $en"+y$e in u.-n $ri"n !ise-ses;
-cc"r!in*ly5 984b-se! clinic"$-+"l"*ic cl-ssi<c-+i"ns bec-.e -n i.$"r+-n+
+""l in s+u!ies ") $ri"n $-+"*enesis in u.-n br-ins -n! in +r-ns*enic .ice
."!els.37571 8ec-use +6" !is+inc+ PL cle-&-*e si+es in PrP2c 1y$es 1 -n! 2
."s+ li7ely s+e. )r". !is+inc+ c"n)"r.-+i"ns5 s".e in&es+i*-+"rs c"n+en!
+-+ PrP2c 1y$es 1 -n! 2 c"!e !is+inc+ $ri"n s+r-ins.3571575580 @"6e&er5 +e
e+er"*enei+y ") s(JI5 -l"n* 6i+ - *r"6in* nu.ber ") s+u!ies inclu!in*
bi"-ss-ys5 -ll su**es+ +-+ +e r-n*e ") $ri"ns c-usin* s(JI eGcee!s +e
nu.ber ") c-+e*"ries rec"*ni:e! 6i+in +e curren+ 984b-se!
clinic"$-+"l"*ic sce.es.81483 #!!i+i"n-lly5 recen+ <n!in*s ") +e c"4
"ccurrence ") PrP2c 1y$es 1 -n! 2 in 40Q "r ."re s(JI c-ses cre-+e! -
c"nun!ru. -n! su**es+e! +-+ +e "ri*in-lly "bser&e! !i;erences 6ere
Au-n+i+-+i&e r-+er +-n Au-li+-+i&e.84489 Hin-lly5 u$ +" 90Q ") br-in PrP2c in
s(JI elu!es 98 -n-lysis bec-use i+ is !es+r"ye! by $r"+ein-se4L +re-+.en+5
6ic is necess-ry +" eli.in-+e PrP( 81. ("nseAuen+ly5 +e c"n)"r.-+i"n "r
r"le ") +is .-F"r $r"+e-se4sensi+i&e (s) )r-c+i"n ") PrP2c in +e $-+"*enesis
") +e !ise-se is - subFec+ ") s$ecul-+i"n.64581590 1us5 n" !irec+ s+ruc+ur-l
!-+- -re -&-il-ble )"r s(JI br-in PrP2c bey"n! +e e&i!ence +-+ i+ is
resis+-n+ +" $r"+e"ly+ic !i*es+i"n. >e&er+eless5 +" !e+er.ine +e )ull
s$ec+ru. ") s(JI $ri"n s+r-ins5 -n! +e c"n)"r.-+i"n-l )e-+ures in +e
$-+"*enic u.-n $ri"n $r"+ein *"&ernin* re$lic-+i"n ") s(JI $ri"ns is
)un!-.en+-l )"r +e r-+i"n-l !e&el"$.en+ ") !i-*n"s+ic -s 6ell -s +er-$eu+ic
s+r-+e*ies.
0" +":
>"&el c"n)"r.-+i"n-l .e+"!s !eri&e! )r". - c"n)"r.-+i"n4!e$en!en+
i..un"-ss-y ((I=)
1ree "bs+-cles -&e sl"6e! $r"*ress in +e rese-rc ") u.-n $ri"ns:
$en"+y$ic &-ri-bili+y ") s(JI "n c".$leG *ene+ic b-c7*r"un!5 bi"s-)e+y
c"ns+r-in+s5 -n! l-c7 ") sui+-ble +""ls )"r s+u!yin* ."lecul-r c-r-c+eris+ics
bey"n! 98 +y$in*. #i.in* +" -!&-nce "ur un!ers+-n!in* ") +e ."lecul-r
$-+"*enesis ") u.-n $ri"n !ise-ses5 6e !e&el"$e! +e c"n)"r.-+i"n4
!e$en!en+ i..un"-ss-y ((I=)56581591 +" !e+er.ine +e c"n)"r.-+i"n-l
r-n*e -n! s+r-in4!e$en!en+ ."lecul-r )e-+ures ") s(JI PrP2c5 <rs+ in $-+ien+s
6" 6ere ".":y*"us )"r c"!"n 129 ") +e PM>P *ene.92 3&en rel-+i&ely
.inu+e &-ri-+i"ns in - s"luble $r"+ein s+ruc+ure c-n be !e+er.ine! by
.e-surin* c"n)"r.-+i"n-l s+-bili+y in - !en-+ur-n+ suc -s 0!n @(l.93
E+ili:in* +is c"nce$+5 6e !esi*ne! - $r"ce!ure in 6ic PrP2c is <rs+
eG$"se! +" !en-+ur-n+ 0!n @(l -n! +en eG$"se! +" eur"$iu.4l-bele! .#b
-*-ins+ +e e$i+"$es i!!en in +e n-+i&e c"n)"r.-+i"n.56 #s +e
c"ncen+r-+i"n ") 0!n @(l incre-ses5 PrP2c !iss"ci-+es -n! un)"l!s )r".
n-+i&e J4see+4s+ruc+ure! -**re*-+es5 -n! ."re e$i+"$es bec".e -&-il-ble
+" -n+ib"!y bin!in*. 1ese eG$eri.en+s in&"l&e ins"luble "li*".eric )"r.s ")
PrP2c5 -n! !en-+ur-+i"n ") +is $r"+ein is irre&ersible in &i+r"; c"nseAuen+ly
+e 0ibbs )ree ener*y c-n*e (e0) ") PrP2c c-nn"+ be c-lcul-+e!.94
1ere)"re 6e c"se ins+e-! +" use +e 0!n @(l &-lue )"un! -+ +e -l)4
.-Gi.-l !en-+ur-+i"n (Y0!n@(lZ1%2) -s - .e-sure ") +e rel-+i&e
c"n)"r.-+i"n-l s+-bili+y ") PrP2c. 1e !i;erences in s+-bili+y re&e-l e&i!ence
") !is+inc+ c"n)"r.-+i"ns ") PrP2c 565 935 94.
1" .e-sure +e c"ncen+r-+i"n ") !i;eren+ )"r.s ") PrP2c -n! )"ll"6 +e
un)"l!in*5 6e use! eur"$iu.4l-bele! .#b 3H495 (e$i+"$e resi!ues 107112)
)"r !e+ec+i"n -n! 8@4 .#b (e$i+"$e resi!ues 175185)96 +" c-$+ure u.-n
PrP2c in - s-n!6ic (I= )"r.-+.81597 1e -n-ly+ic-l sensi+i&i+y -n! s$eci<ci+y
") +e "$+i.i:e! (I= )"r !e+ec+i"n ") PrP2c 6-s $re&i"usly re$"r+e! by us -n!
"+ers in nu.er"us $ublic-+i"ns565815915984100 -n! -s been s"6n +" be
-s l"6 -s P500 )* (P20 -++"."les) ") PrP2c 6ic is si.il-r +" +e sensi+i&i+y
") u.-n $ri"n bi"-ss-y in 1*('@u2')5378%Prn$0%0 .ice.81 8ec-use (I= is
n"+ !e$en!en+ "n $r"+e-se +re-+.en+5 i+ -ll"6e! us +" -!!ress )un!-.en+-l
Aues+i"ns c"ncernin* +e c"ncen+r-+i"n -n! c"n)"r.-+i"n ") !i;eren+
is")"r.s ") s(JI PrP2c5 inclu!in* $r"+e-se4sensi+i&e (s) -n! $r"+e-se4resis+-n+
(r)PrP2c 92.
1e !iss"ci-+i"n -n! un)"l!in* ") PrP2c in +e $resence ") incre-sin*
c"ncen+r-+i"n ") 0!n @(l c-n be !escribe! -s )"ll"6s:
YPrP2cZn f YsPrP2cZn f iPrP f uPrP
6ere YPrP2cZn -re n-+i&e -**re*-+es ") PrP2c5 YsPrP2cZn -re s"luble
$r"+e-se4sensi+i&e "li*".ers ") PrP2c5 iPrP is -n in+er.e!i-+e5 -n! uPrP is
c".$le+ely un)"l!e! (!en-+ure!) PrP.53557594 1e (I= ."ni+"rs +e *l"b-l
+r-nsi+i"n )r". n-+i&e -**re*-+es +" )ully !en-+ure! ."n".ers ") PrP2c. =n
c"n+r-s+5 +e 984b-se! +ecniAues ."ni+"r ei+er +e $-r+i-l s"lubili:-+i"n ")
PrP2c 101 "r c"n&ersi"n ") rPrP2c +" $r"+e-se4sensi+i&e c"n)"r.ers72 -)+er
eG$"sure +" !en-+ur-n+. #s - resul+5 +e s+-bili+y !-+- "n s"luble $r"+e-se4
sensi+i&e "li*".ers -n! in+er.e!i-+es ") PrP2c c-nn"+ be "b+-ine! 6i+ 98
+ecniAues -n! .-y eG$l-in s".e .-r7e!ly !i;eren+ &-lues.102
0" +":
2+ruc+ur-l e+er"*enei+y ") s(JI PrP2c -n! +e r"le ") sPrP2c in $-+"*enesis
Kur recen+ <n!in* ") 64)"l! !i;erence in c"ncen+r-+i"ns ") PrP2c be+6een
1y$e 1 -n! 1y$e 2 PrP2c(129') in +e )r"n+-l c"r+eG 6-s sur$risin*5 e&en
+"u* s".e &-ri-bili+y 6-s +" be eG$ec+e! !ue +" !i;erences in +e
$re!".in-n+ly -;ec+e! -re-s in !is+inc+ s(JI $en"+y$es.81592 '"re"&er5
+e -&er-*e le&els ") PrP2c 6ere u$ +" 1004)"l! l"6er +-n +"se in s+-n!-r!
l-b"r-+"ry $ri"n ."!els suc -s 2yri-n -.s+ers in)ec+e! 6i+ 2c237
$ri"ns56; -n! +"*e+er 6i+ +e u$ +" 1004)"l! &-ri-bili+y 6i+in e-c
$en"+y$ic *r"u$5 +ese l"6er le&els ") PrP2c .-y eG$l-in 6y s".e s(JI
c-ses -re !iBcul+ +" +r-ns.i+5 -n! 6y l"6er en!$"in+ +i+ers -re "b+-ine!
6i+ u.-n $ri"ns in +r-ns*enic .ice eG$ressin* u.-n "r ci.eric PrP( 375
715 815 103.
E$ +" 90Q ") +e $-+"*enic $ri"n $r"+ein in s(JI is $r"+e-se4sensi+i&e81 -n!
6e )"un! +e i*es+ c"ncen+r-+i"ns in 1y$e 2 PrP2c(129') (Hi*. 1).92 1e
br"-! r-n*e ") -bs"lu+e -n! rel-+i&e le&els ") rPrP2c -n! sPrP2c ";ers
e&i!ence ") - br"-! s$ec+ru. ") PrP2c ."lecules !i;erin* in $r"+e-se
sensi+i&i+y in e-c *r"u$ 6i+ -n i!en+ic-l $"ly."r$is. -+ c"!"n 129 ") +e
PM>P *ene -n! -n i!en+ic-l 98 $-++ern. '"re"&er5 +ese <n!in*s si*n-l +e
eGis+ence ") - &-rie+y ") s(JI PrP2c c"n)"r.ers; -n! since $r"+e-se
sensi+i&i+y is "ne ") +e c-r-c+eris+ics ") $ri"n s+r-ins5 +ey -ls" su**es+ +-+
!is+inc+ s(JI $ri"n s+r-ins eGis+.5655758158251045105
<*ure $ri"4641084*1
Hi*ure 1. 1e rel-+i"nsi$ be+6een !ur-+i"n ") +e !ise-se5 (le)+ $-nel)
c"ncen+r-+i"n5 -n! (ri*+ $-nel) c"n)"r.-+i"n-l s+-bili+y ") sPrP2c c"n)"r.ers
in s(JI $-+ien+s 6i+ !i;eren+ 98 $-++erns -n! PM>P *ene $"ly."r$is.s.92
1e s+-bili+y ") ...
1e e+er"*enei+y ") PrP2c c"n)"r.-+i"ns 6e )"un! 6i+ (I= 6i+in s(JI
$-+ien+s ".":y*"us )"r c"!"n 129 $ly."r$is. ") +e PM>P *ene is
re.-r7-ble5 -&in* - r-n*e c"rres$"n!in* +" +-+ ") s+-bili+ies )"un! in
-$$r"Gi.-+ely 30 !is+inc+ s+r-ins ") !e4n"&" -n! n-+ur-l l-b"r-+"ry r"!en+
$ri"ns s+u!ie! u$ +" n"6.565725925106 1e in+ri*uin* !i;eren+i-l e;ec+ ") PL
+re-+.en+ 6i+ incre-sin* s+-bili+y ") +y$e 1 -n! !ecre-sin* s+-bili+y ") 1y$e 2
PrP2c(129') su**es+s +-+ in c"n+r-s+ +" 1y$e 15 +e $r"+e-se4resis+-n+ c"re
") 1y$e 2 6-s $r")"un!ly !es+-bili:e!. 1"*e+er 6i+ +e incre-se! )reAuency
") eG$"se! e$i+"$es in c"!"n 129 '' s-.$les 6i+ 1y$e 2 rPrP2c -)+er PL
+re-+.en+5 +ese "bser&-+i"ns .-y in!ic-+e "ne ") +ree $"ssibili+ies: +-+ +e
li*-n! $r"+ec+in* +e 3H4 e$i+"$e 6-s re."&e! by PL +re-+.en+; +-+ e$i+"$e
108112 6-s $r"+ec+e! by +e >4+er.inus ") PrP2c; "r +-+ c"n)"r.-+i"n-l
+r-nsi+i"n resul+e! in ."re eG$"se! 108112 e$i+"$e. 9e+er +e e$i+"$e
in!r-nce in un!i*es+e! PrP2c is +e resul+ ") li$i!5 *lyc"s-.in"*lyc-n5
nucleic -ci!5 "r $r"+ein bin!in* +" +e c"n)"r.ers uniAue +" +e ''2 s(JIH
PrP2c re.-ins +" be es+-blise!. 2ince s(JI c-ses 6i+ 1y$e 2 PrP2c(129')
-&e re.-r7-bly eG+en!e! !ise-se !ur-+i"ns5 +e ."lecul-r .ec-nis.
un!erlyin* +ese e;ec+s c-lls )"r !e+-ile! in&es+i*-+i"n. (u.ul-+i&ely5 "ur
<n!in*s in!ic-+e +-+ s(JI PrP2c eGibi+s eG+ensi&e c"n)"r.-+i"n-l
e+er"*enei+y -n! su**es+ +-+ - 6i!e s$ec+ru. ") s(JI $ri"ns c-use +e
!ise-se. 9e+er +is e+er"*enei+y "ri*in-+es in - s+"c-s+ic .is)"l!in*
$r"cess +-+ *ener-+es .-ny !is+inc+ sel)4re$lic-+in* c"n)"r.-+i"ns37562 "r
in - c".$leG $r"cess ") e&"lu+i"n-ry selec+i"n !urin* !e&el"$.en+ ") +e
!ise-se73 re.-ins +" be es+-blise!.
9e !isc"&ere! $r"+e-se4sensi+i&e c"n)"r.ers ") PrP2c 6ile !e&el"$in* -
c"n)"r.-+i"n4!e$en!en+ i..un"-ss-y ((I=)5 6ic !"es n"+ reAuire
$r"+e"ly+ic !e*r-!-+i"n ") ubiAui+"us PrP( 56. #l+"u* +e "ri*in-l !e<ni+i"n
") sPrP2c 6-s $urely "$er-+i"n-l5 c"nsi!er-ble -!!i+i"n-l !-+- !e."ns+r-+e
+-+ (1) sPrP2c re$lic-+es in &i&" -n! in &i+r" -s -n in&-ri-n+ -n! .-F"r
)r-c+i"n ") PrP2c; (2) sPrP2c se$-r-+es )r". rPrP2c in i* s$ee!
cen+ri)u*-+i"n5 -n! (3) +e $r"+e"ly+ic sensi+i&i+y ") PrP2c c-n reli-bly
!i;eren+i-+e &-ri"us $ri"n s+r-ins.5655758158251045105 #ccu.ul-+i"n ")
sPrP2c $rece!es $r"+e-se4resis+-n+ $r"!uc+ (rPrP2c) in $ri"n in)ec+i"n645107;
-n! u$ +" 90Q ") PrP2c -ccu.ul-+in* in (JI br-ins c"nsis+s ") sPrP2c 81.
1us5 +e !e+ec+i"n by (I= ") sPrP2c -s - !ise-se4s$eci<c .-r7er is 6i!ely
re*-r!e! -s - ."re reli-ble b-sis )"r !i-*n"sin* $ri"n !ise-ses. 1is
i.$r"&e! !e+ec+i"n le! +" +e !isc"&ery ") - ne6 u.-n $ri"n !is"r!er5
&-ri-bly $r"+e-se4sensi+i&e $ri"n"$-+y (VP2Pr).175565815905108 =+ is
n"+e6"r+y +-+ syn+e+ic $ri"ns *ener-+e! in &i+r" !urin* $"ly.eri:-+i"n ")
rec".bin-n+ ."use PrP in+" -.yl"i! <bers $r"!uce! $ri"ns c".$"se!
eGclusi&ely ") sPrP2c u$"n in"cul-+i"n in+" 6il! .ice.106
Kur recen+ !-+- in!ic-+e +-+ +e le&els -s 6ell -s s+-bili+y ") sPrP2c -re -
*""! $re!ic+"r ") +e $r"*ressi"n r-+e in s(JI (Hi*. 1).92 Ies$i+e +e
ine&i+-ble inVuence ") &-ri-ble *ene+ic b-c7*r"un! -n! +e $"+en+i-l
!iBcul+ies in e&-lu-+in* ini+i-l sy.$+".s5 +e !ise-se $r"*ressi"n r-+e -n!
incub-+i"n +i.e F"in+ly re$resen+ -n i.$"r+-n+ $-r-.e+er5 6ic is inVuence!
by re$lic-+i"n r-+e5 $r"$-*-+i"n5 -n! cle-r-nce ") $ri"ns )r". +e
br-in.645109 1e c"rrel-+i"ns -."n* +e le&els ") sPrP2c5 +e s+-bili+y ")
sPrP2c5 -n! +e !ur-+i"n ") +e !ise-se )"un! in +is s+u!y -ll in!ic-+e +-+
sPrP2c c"n)"r.ers $l-y -n i.$"r+-n+ r"le in +e $-+"*enesis. 9en sPrP2c is
less s+-ble +-n rPrP2c5 +e !i;erence in s+-bili+y c"rrel-+es 6i+ less
-ccu.ul-+e! sPrP2c -n! s"r+er !ur-+i"n ") +e !ise-se. ("n&ersely5 6en
sPrP c"n)"r.ers -re ."re s+-ble +-n rPrP2c5 6e "bser&e! +e "$$"si+e e;ec+
?."re -ccu.ul-+e! sPrP2c -n! eG+en!e! !ise-se !ur-+i"n (Hi*. 1).
=n l-b"r-+"ry r"!en+ $ri"n ."!els5 6e )"un! +-+ le&els ") sPrP2c &-rie! 6i+
+e incub-+i"n +i.e ") +e !ise-se56 -n! 6e y$"+esi:e! +-+ +e ."lecul-r
.ec-nis. ") +is lin7 .-y be rel-+e! +" +e re$lic-+i"n "r cle-r-nce r-+e ")
$ri"ns.56564581 Kur recen+ !-+- "n s(JI $ri"ns eG+en! +is "bser&-+i"n -n!
in!ic-+e +-+ i*er le&els ") less s+-ble sPrP2c le-! +" )-s+er $r"*ressi"n ")
+e !ise-se.92 1ese "bser&-+i"ns -re in -cc"r! 6i+ +e eG$eri.en+s "n
ye-s+ $ri"ns -n! su**es+ +-+ +e s+-bili+y ") .is)"l!e! $r"+ein is in&ersely
rel-+e! +" +e re$lic-+i"n r-+e.110 #l+"u* +e ."!ul-+in* e;ec+ ") $ri"n
cle-r-nce in +e .-..-li-n br-ins is li7ely564 +e !-+- )r". b"+ ye-s+ -n!
u.-n $ri"ns le-! +" +e y$"+esis +-+ +e less s+-ble $ri"ns re$lic-+e
)-s+er by eG$"sin* ."re -&-il-ble si+es )"r *r"6+ ") +e -**re*-+es. =n
.-..-li-n $ri"ns5 +is e;ec+ le-!s +" s"r+er incub-+i"n +i.e -n! )-s+er
$r"*ressi"n ") +e !ise-se.
0" +":
Hu+ure !irec+i"ns
#!!i+i"n-l s+e$s -re necess-ry +" i.$r"&e "ur un!ers+-n!in* ") +e
$en"+y$ic !i&ersi+y ") s(JI. Kne s+e$ is +" !e+er.ine 6e+er +e .iGe! 98
$-++erns ") 1y$e 12 rPrP2c in +e s-.e "r !i;eren+ -n-+".ic-l -re-s
re$resen+ - uniAue c"n)"r.-+i"n "r - .iG+ure ") c"n)"r.ers5 -n! +" .-$ +e
!is+ribu+i"n in +e in!i&i!u-l br-in.89 #!!i+i"n-lly5 n"&el c"n)"r.-+i"n-l
-$$r"-ces usin* +-n!e. $r"+ein .is)"l!in* cyclic -.$li<c-+i"n (P'(#) -n!
(I= s"ul! -ll"6 -n-lysis ") +e i.$-c+ ") !i;eren+ PrP2c $"ly."r$is.s -n!
c"n)"r.-+i"ns "n +e re$lic-+i"n r-+e ") u.-n $ri"ns. 2uc s+u!ies -&e
cle-rly br"-!er i.$lic-+i"ns5 -s recen+ !-+- su**es+ +-+ +e $r"cess ")
in+ercellul-r in!uc+i"n ") $r"+ein .is)"l!in* is rele&-n+ in +e $-+"*enesis ")
*r"6in* nu.ber ") "+er neur"!e*ener-+i&e !ise-ses.39443
0" +":
#c7n"6le!*.en+s
1e -u+"rs +-n7 Pierlu*i 0-.be++i -n! 9i+"l! 2ure6ic: )"r enc"ur-*e.en+
-n! s+i.ul-+in* !iscussi"ns. 1is 6"r7 6-s su$$"r+e! by *r-n+s )r". >=# (#04
14359)5 >=>I2 (>2074317)5 (I( (EM8%((E515004)5 -n! +e (-rles 2.
8ri++"n Hun!.
0" +":
0l"ss-ry
#bbre&i-+i"ns:
#,2
-.y"+r"$ic l-+er-l scler"sis
(I=
c"n)"r.-+i"n4!e$en!en+ i..un"-ss-y
(JI
(reu+:)el!+4J-7"b !ise-se
022
0ers+.-nn42+r]ussler42cein7er syn!r".e
PrP
$ri"n $r"+ein
PrP(
n"r.-l "r cellul-r $ri"n $r"+ein
PrP2c
$-+"*enic $ri"n $r"+ein
PM>P
$ri"n $r"+ein *ene
rPrP2c
$r"+e-se4resis+-n+ c"n)"r.ers ") $-+"*enic $ri"n $r"+ein
sPrP2c
$r"+e-se4sensi+i&e c"n)"r.ers ") $-+"*enic $ri"n $r"+ein
s(JI
s$"r-!ic (reu+:)el!+4J-7"b !ise-se
2H=
s$"r-!ic )-+-l ins".ni-
VP2Pr
&-ri-ble $r"+e-se4sensi+i&e $ri"n"$-+y
0" +":
H""+n"+es
Pre&i"usly $ublise! "nline:
666.l-n!esbi"science.c".%F"urn-ls%$ri"n%-r+icle%18666
0" +":
Me)erences
1. Prusiner 28. >"&el $r"+ein-ce"us in)ec+i"us $-r+icles c-use scr-$ie.
2cience. 1982;216:13644. !"i: 10.1126%science.6801762. YPub'e!Z Y(r"ss
Me)Z
2. 0-F!use7 I(. 2l"64&irus in)ec+i"ns ") +e ner&"us sys+e.. > 3n*l J 'e!.
1967;276:392400. !"i: 10.1056%>3J'196702162760708. YPub'e!Z Y(r"ss
Me)Z
3. '"n-ri ,5 (en 205 8r"6n P5 P-rci P5 Pe+ersen M85 'i7"l J5 e+ -l. H-+-l
)-.ili-l ins".ni- -n! )-.ili-l (reu+:)el!+4J-7"b !ise-se: !i;eren+ $ri"n
$r"+eins !e+er.ine! by - I># $"ly."r$is.. Pr"c >-+l #c-! 2ci E 2 #.
1994;91:283942. !"i: 10.1073%$n-s.91.7.2839. YP'( )ree -r+icleZ YPub'e!Z
Y(r"ss Me)Z
4. P-rci P5 0iese #5 (-$ell-ri 25 8r"6n P5 2cul:42c-e;er 95 9in!l K5 e+ -l.
(l-ssi<c-+i"n ") s$"r-!ic (reu+:)el!+4J-7"b !ise-se b-se! "n ."lecul-r -n!
$en"+y$ic -n-lysis ") 300 subFec+s. #nn >eur"l. 1999;46:22433. !"i:
10.1002%153148249(199908)46:2g224::#=I4#>#12R3.0.(K;249. YPub'e!Z
Y(r"ss Me)Z
5. 0-.be++i P5 L"n* \5 `"u 95 P-rci P5 (en 20. 2$"r-!ic -n! )-.ili-l (JI:
cl-ssi<c-+i"n -n! c-r-c+eris-+i"n. 8r 'e! 8ull. 2003;66:21339. !"i:
10.1093%b.b%66.1.213. YPub'e!Z Y(r"ss Me)Z
6. Prusiner 285 e!. Pri"n 8i"l"*y -n! Iise-ses. ("l! 2$rin* @-rb"r: ("l!
2$rin* @-rb"r ,-b"r-+"ry Press5 2004.
7. @"l.-n M(5 8el-y 3I5 (ris+ensen LW5 '-!!"G M#5 'inin" #'5 H"l7e.- #'5
e+ -l. @u.-n $ri"n !ise-ses in +e Eni+e! 2+-+es. P,"2 Kne. 2010;5:e8521.
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8. '-s+ers (,5 0-F!use7 I(5 0ibbs (J Jr.5 8ern"uilli (5 #ser I'. H-.ili-l
(reu+:)el!+4J-7"b !ise-se -n! "+er )-.ili-l !e.en+i-s: -n inAuiry in+"
$"ssible ."!els ") &irus4in!uce! )-.ili-l !ise-ses. =n: Prusiner 285 @-!l"6 9J5
e!s. 2l"6 1r-ns.issible Iise-ses ") +e >er&"us 2ys+e.5 V"l 1. >e6 W"r7:
#c-!e.ic Press5 1979:143494.
9. J-7"b #. hber eine !er .ul+i$len 27ler"se 7linisc n-es+een!e
3r7r-n7un* !es èn+r-lner&ensys+e.s (s$-s+isce Pseu!"s7ler"se) .i+
be.er7ens6er+e. -n-+".isce. 8e)un!e. 'i++eilun* eines &ier+en H-lles.
'e! Llin ('unic) 1921;17:3726.
10. (reu+:)el!+ @0. hber eine ei*en-r+i*e er!)ir.i*e 3r7r-n7un* !es
èn+r-lner&ensys+e.s. ` 0es-.+e >eur"l Psyci-+r. 1920;57:118. !"i:
10.1007%8H02866081. Y(r"ss Me)Z
11. '-s+ers (,5 0-F!use7 I(. 1e s$ec+ru. ") (reu+:)el!+4J-7"b !ise-se -n!
&irus4in!uce! sub-cu+e s$"n*i)"r. ence$-l"$-+ies. Mecen+ #!&
>eur"$-+"l. 1982;2:13963.
12. 9ils"n 2#L. 2yn!r".e ") J-7"b: ("r+ic"4s+ri-+"4s$in-l !e*ener-+i"n.
,"n!"n: 3!6-r! #rn"l!5 1940.
13. Lirscb-u. 9M. J-7"b4(reu+:)el!+ Iise-se. #.s+er!-.: 3lse&ier5 1968.
14. >e&in 25 'c'3>3'3W 9@5 8er.-n 25 J"nes IP. 2ub-cu+e s$"n*i)"r.
ence$-l"$-+y44- sub-cu+e )"r. ") ence$-l"$-+y -++ribu+-ble +" &-scul-r
!ys)unc+i"n (s$"n*i)"r. cerebr-l -+r"$y) 8r-in. 1960;83:51964. !"i:
10.1093%br-in%83.4.519. YPub'e!Z Y(r"ss Me)Z
15. 0-.be++i P5 P-rci P. =ns".ni- in $ri"n !ise-ses: s$"r-!ic -n! )-.ili-l. >
3n*l J 'e!. 1999;340:16757. !"i: 10.1056%>3J'199905273402111.
YPub'e!Z Y(r"ss Me)Z
16. '-s+ri-nni J5 >iG"n H5 ,-y:er M5 Ie#r."n! 2J5 Prusiner 28. H-+-l s$"r-!ic
ins".ni-: )-+-l )-.ili-l ins".ni- $en"+y$e 6i+"u+ - .u+-+i"n ") +e $ri"n
$r"+ein *ene. >eur"l"*y. 1997;48(2u$$l.):#296.
17. 0-.be++i P5 I"n* `5 Wu-n J5 î-" ^5 èn* '5 #lse7lee #5 e+ -l. # n"&el
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s+u!y ") -n -cu+e $r"*ressi&e !e*ener-+i&e !ise-se ") +e cen+r-l ner&"us
sys+e. -."n* n-+i&es ") +e 3-s+ern @i*l-n!s ") >e6 0uine-. #. J 'e!.
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$"$ul-+i"n. > 3n*l J 'e!. 1957;257:9748. !"i:
10.1056%>3J'195711142572005. YPub'e!Z Y(r"ss Me)Z
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21. @-!l"6 9J. 2cr-$ie -n! 7uru. ,-nce+. 1959;274:28990. !"i:
10.1016%2014046736(59)9208141. Y(r"ss Me)Z
22. 0ibbs (J5 Jr.5 0-F!use7 I(5 #ser I'5 #l$ers 'P5 8ec7 35 I-niel P'5 e+ -l.
(reu+:)el!+4J-7"b !ise-se (s$"n*i)"r. ence$-l"$-+y): +r-ns.issi"n +" +e
ci.$-n:ee. 2cience. 1968;161:3889. !"i: 10.1126%science.161.3839.388.
23. 0-F!use7 I(5 0ibbs (J5 Jr.5 #l$ers '. 3G$eri.en+-l +r-ns.issi"n ") - Luru4
li7e syn!r".e +" ci.$-n:ees. >-+ure. 1966;209:7946. !"i:
10.1038%209794-0. YPub'e!Z Y(r"ss Me)Z
24. '-s+ers (,5 0-F!use7 I(5 0ibbs (J.5 Jr. (reu+:)el!+4J-7"b !ise-se &irus
is"l-+i"ns )r". +e 0ers+.-nn42+r]ussler syn!r".e 6i+ -n -n-lysis ") +e
&-ri"us )"r.s ") -.yl"i! $l-Aue !e$"si+i"n in +e &irus4in!uce! s$"n*i)"r.
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-l. Pri"n $r"+ein e+er"*enei+y in s$"r-!ic bu+ n"+ &-ri-n+ (reu+:)el!+4J-7"b
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87. ,e6is V5 @ill #H5 Llu* 0'5 8"y! #5 '-s+ers (,5 ("llins 2J. #us+r-li-n
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$r"<les. >eur"l"*y. 2005;65:1138. !"i:
10.1212%01.6nl.0000167188.65787.-0. YPub'e!Z Y(r"ss Me)Z
88. 2c"c 05 2ee*er @5 8"*"ussl-&s7y J5 1"ln-y '5 J-n:er M(5 #*u::i #5 e+ -l.
#n-lysis ") $ri"n s+r-ins by PrP2c $r"<lin* in s$"r-!ic (reu+:)el!+4J-7"b
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89. (-li =5 (-s+ell-ni M5 #lse7lee #5 ("en W5 8le&ins J5 Wu-n J5 e+ -l. ("4
eGis+ence ") scr-$ie $ri"n $r"+ein +y$es 1 -n! 2 in s$"r-!ic (reu+:)el!+4J-7"b
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90. (r"nier 25 0r"s >5 1-++u. '@5 J-c7s"n 025 (l-r7e #M5 ("llin*e J5 e+ -l.
Ie+ec+i"n -n! c-r-c+eri:-+i"n ") $r"+ein-se L4sensi+i&e !ise-se4rel-+e! $ri"n
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92. Li. (5 @-l!i.-n 15 ("en W5 (en 95 8le&ins J5 2y '25 e+ -l. Pr"+e-se4
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s$"r-!ic (reu+:)el!+4J-7"b !ise-se -re in!ic-+"r ") $r"*ressi"n r-+e. P,"2
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94. 2-)-r J5 M"ller PP5 0-F!use7 I(5 0ibbs (J.5 Jr. 2cr-$ie -.yl"i! ($ri"n)
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*l"bule )"l!in* in+er.e!i-+e. 8i"ce.is+ry. 1994;33:837583. !"i:
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95. L-scs-7 MJ5 Mubens+ein M5 'er: P#5 1"nn-4Ie'-si '5 Hers7" M5 (-r$ M=5 e+
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$r"+eins. J Vir"l. 1987;61:368893. YP'( )ree -r+icleZ YPub'e!Z
96. `-nuss" 05 ,iu I5 Herr-ri 25 @e*yi =5 Win ^5 #*u::i #5 e+ -l. Pri"n $r"+ein
eG$ressi"n in !i;eren+ s$ecies: -n-lysis 6i+ - $-nel ") ne6 .#bs. Pr"c >-+l
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Pri"n $r"+eins in sub$"$ul-+i"ns ") 6i+e bl""! cells )r". $-+ien+s 6i+
s$"r-!ic (reu+:)el!+4J-7"b !ise-se. ,-b =n&es+. 2009;89:62435. !"i:
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98. 8ell"n #5 2ey)er+48r-n!+ 95 ,-n* 95 8-r"n @5 0riner #5 Vey '. =.$r"&e!
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6i+ en-nce! sensi+i&i+y. J 0en Vir"l. 2003;84:19215. !"i:
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99. 1-c7r-y #'5 @"$7ins ,5 8uF!"s" M. Pr"+ein-se L4sensi+i&e !ise-se4
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i..un"-ss-y. 8i"ce. J. 2007;401:47583. !"i: 10.1042%8J20061264. YP'(
100. J"nes '5 Pe!en #@5 Wull @5 9i*+ I5 8is"$ '15 Pr"6se (V5 e+ -l. @u.-n
$l-+ele+s -s - subs+r-+e s"urce )"r +e in &i+r" -.$li<c-+i"n ") +e -bn"r.-l
$ri"n $r"+ein (PrP) -ss"ci-+e! 6i+ &-ri-n+ (reu+:)el!+4J-7"b !ise-se.
1r-ns)usi"n. 2009;49:37684. !"i: 10.1111%F.153742995.2008.01954.G.
101. Pirisinu ,5 Ii 8-ri '5 '-rc"n 25 V-cc-ri 05 IO#*"s+in" (5 H-::i P5 e+ -l. #
ne6 .e+"! )"r +e c-r-c+eri:-+i"n ") s+r-in4s$eci<c c"n)"r.-+i"n-l s+-bili+y
") $r"+e-se4sensi+i&e -n! $r"+e-se4resis+-n+ PrP. P,"2 Kne. 2010;5:e12723.
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102. ("i WP5 Pe!en #@5 0riner #5 =r"nsi!e J95 @e-! '9. Iis+inc+ s+-bili+y
s+-+es ") !ise-se4-ss"ci-+e! u.-n $ri"n $r"+ein i!en+i<e! by c"n)"r.-+i"n4
!e$en!en+ i..un"-ss-y. J Vir"l. 2010;84:120308. !"i: 10.1128%JV=.010574
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103. 8is"$ '15 9ill M05 '-ns"n J(. Ie<nin* s$"r-!ic (reu+:)el!+4J-7"b
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2010;107:1200510. !"i: 10.1073%$n-s.1004688107. YP'( )ree -r+icleZ
104. P-s+r-n- '#5 2-Fn-ni 05 Knis7" 85 (-s+ill- J5 '"r-les M5 2"+" (5 e+ -l.
=s"l-+i"n -n! c-r-c+eri:-+i"n ") - $r"+ein-se L4sensi+i&e PrP2c )r-c+i"n.
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105. >"+-ri 25 2+r-..iell" M5 (-$ell-ri 25 0iese #5 (esc-++i '5 0r-ssi J5 e+ -l.
(-r-c+eri:-+i"n ") +runc-+e! )"r.s ") -bn"r.-l $ri"n $r"+ein in (reu+:)el!+4
J-7"b !ise-se. J 8i"l (e.. 2008;283:3055765. !"i:
10.1074%Fbc.'801877200. YP'( )ree -r+icleZ YPub'e!Z Y(r"ss Me)Z
106. ("lby I95 9-in M5 8-s7-7"& =V5 ,e*n-.e 05 P-l.er (05 >*uyen @K5 e+
-l. Pr"+e-se4sensi+i&e syn+e+ic $ri"ns. P,"2 P-+"*. 2010;6:e1000736. !"i:
10.1371%F"urn-l.$$-+.1000736. YP'( )ree -r+icleZ YPub'e!Z Y(r"ss Me)Z
107. '-llucci 0M5 9i+e 'I5 H-r.er '5 Iic7ins"n #5 L-+un @5 P"6ell #I5 e+
-l. 1-r*e+in* cellul-r $ri"n $r"+ein re&erses e-rly c"*ni+i&e !e<ci+s -n!
neur"$ysi"l"*ic-l !ys)unc+i"n in $ri"n4in)ec+e! .ice. >eur"n. 2007;53:325
35. !"i: 10.1016%F.neur"n.2007.01.005. YPub'e!Z Y(r"ss Me)Z
108. J"nes '5 Pe!en #@5 Pr"6se (V5 0riner #5 '-ns"n J(5 1urner ',5 e+ -l. =n
&i+r" -.$li<c-+i"n -n! !e+ec+i"n ") &-ri-n+ (reu+:)el!+4J-7"b !ise-se PrP2c. J
P-+"l. 2007;213:216. !"i: 10.1002%$-+.2204. YPub'e!Z Y(r"ss Me)Z
109. Prusiner 285 2c"++ 'M5 Ie#r."n! 2J5 (-rls"n 0. 1r-ns.issi"n -n!
re$lic-+i"n ") $ri"ns. =n: Prusiner 285 e!. Pri"n 8i"l"*y -n! Iise-ses. ("l!
2$rin* @-rb"r: ("l! 2$rin* @-rb"r ,-b"r-+"ry Press5 2004:1874242.
110. 1-n-7- '5 ("llins 2M5 1"y-.- 8@5 9eiss.-n J2. 1e $ysic-l b-sis ")
"6 $ri"n c"n)"r.-+i"ns !e+er.ine s+r-in $en"+y$es. >-+ure.
2006;442:5859. !"i: 10.1038%n-+ure04922. YPub'e!Z Y(r"ss Me)Z
#r+icles )r". Pri"n -re $r"&i!e! ere c"
Jurnal 1P
Prion. 2010 E$t7#e$; >(>): 26527>.
Publi!e" online 2010 E$tober 1. "oi: 10.>161&pri.>.>.1%125
PM()#: PM(%268959
Nanoimaging for prion related diseases
AleLe2 = 6r+nolobo"te@,
1
AleL+n"er M Portillo,
1
1+nM+ #e$0ert7G+u"i',
2
=ol0er
#e$0ert,
2,%
+n" Yuri 3 32ub$!en0o
1
Go to:
Abstract
Mi?ol"in' +n" +''re'+tion o? prion protein i lin0e" to + number o? neuro"e'ener+ti@e
"ior"er u$! + (reut<?el"t7-+$ob "ie+e ((-#) +n" it @+ri+nt: 6uru, Gertm+nn7
*tr+uler7*$!ein0er 2n"rome +n" ?+t+l ?+mili+l inomni+. )n prion "ie+e, in?e$tiou
p+rti$le +re protein t!+t prop+'+te b2 tr+nmittin' + mi?ol"e" t+te o? + protein, le+"in'
to t!e ?orm+tion o? +''re'+te +n" ultim+tel2 to neuro"e'ener+tion. Prion p!enomenon i
not retri$te" to !um+n. 1!ere +re + number o? prion7rel+te" "ie+e in + @+riet2 o?
m+mm+l, in$lu"in' bo@ine pon'i?orm en$ep!+lop+t!2 (/*:, +lo 0no4n + om+" $o4
"ie+ep) in $+ttle. All 0no4n prion "ie+e, $olle$ti@el2 $+lle" $r'n%("%%"-!& %pon1"or(
&n#&p3'!op'$3"&% (1*:), +re untre+t+ble +n" ?+t+l. Prion protein 4ere +lo ?oun" in
ome ?un'i 4!ere t!e2 +re reponible ?or !erit+ble tr+it. Prion protein in ?un'i +re
e+il2 +$$eible +n" pro@i"e + po4er?ul mo"el ?or un"ert+n"in' t!e 'ener+l prin$iple
o? prion p!enomenon +n" mole$ul+r me$!+nim o? m+mm+li+n prion "ie+e.
Preentl2, e@er+l ?un"+ment+l Duetion rel+te" to prion rem+in un+n4ere". Por
eL+mple, it i not $le+r !o4 prion $+ue t!e "ie+e. Et!er un0no4n in$lu"e t!e n+ture
+n" tru$ture o? in?e$tiou +'ent +n" !o4 prion repli$+te. Gener+ll2, t!e p!enomenon o?
mi?ol"in' o? t!e prion protein into in?e$tiou $on?orm+tion t!+t !+@e t!e +bilit2 to
prop+'+te t!eir propertie @i+ +''re'+tion i o? i'ni?i$+nt interet. #epite t!e $ru$i+l
import+n$e o? mi?ol"in' +n" +''re'+tion, @er2 little i $urrentl2 0no4n +bout t!e
mole$ul+r me$!+nim o? t!ee pro$ee. ;!ile t!ere i +n +pp+rent $riti$+l nee" to
tu"2 mole$ul+r me$!+nim un"erl2in' mi?ol"in' +n" +''re'+tion, t!e "et+ile"
$!+r+$teri<+tion o? t!ee in'le mole$ule pro$ee i !in"ere" b2 t!e limit+tion o?
$on@ention+l met!o". Alt!ou'! ome iue rem+in unreol@e", mu$! pro're !+ been
re$entl2 m+"e prim+ril2 "ue to t!e +ppli$+tion o? n+noim+'in' tool. 1!e ue o?
n+noim+'in' met!o" !o4 're+t promie ?or un"ert+n"in' t!e mole$ul+r me$!+nim
o? prion p!enomenon, poibl2 le+"in' to4+r" e+rl2 "i+'noi +n" e??e$ti@e tre+tment o?
t!ee "e@+t+tin' "ie+e. 1!i re@ie4 +rti$le umm+ri<e re$ent report 4!i$! +"@+n$e"
our un"ert+n"in' o? t!e prion p!enomenon t!rou'! t!e ue o? n+noim+'in' met!o".
/ey words4 protein mi?ol"in', prion, +tomi$ ?or$e mi$ro$op2, n+nome"i$ine, ?or$e
pe$tro$op2
Go to:
&tructure of Amyloid
*i'ni?i$+nt pro're !+ been m+"e in un"ert+n"in' t!e tru$ture o? +''re'+te" pe$ie
+t t!e +tomi$ le@el uin' bot! $omput+tion+l mo"elin' +n" eLperiment+l tu"ie u$! +
^7r+2 $r2t+llo'r+p!2 +n" oli"7t+te 5M8. )t i 4i"el2 +$$epte" t!+t t!e in?e$tiou ?orm
o? prion i el?7prop+'+tin' ?ibrill+r or +m2loi" PrP.
1
1!e ?orm+tion o? +m2loi" !+ been
ti'!tl2 lin0e" to t!e "e@elopment o? t!e "ie+e. Am2loi" !+re $ommon tru$tur+l
?e+ture +n" biop!2i$+l propertie, in$lu"in' bin"in' o? pe$i?i$ "2e, elon'+te"
morp!olo'2 +n" nu$le+tion7"epen"ent 0ineti$ o? +''re'+tion. /+e" on oli"7t+te 5M8
+n" ^7r+2 $r2t+llo'r+p!2 "+t+, t!e un"erl2in' tru$ture o? prion +m2loi" 4+ ?oun" to
!+re $ommon tru$tur+l ?e+ture. 1!e2 $ont+in imil+rl2 +rr+n'e" p+r+llel m7!eet
p+$0e" in re'iter ?or u$! "i??erent prion protein + .re2p1789 (t!e b+i o? t!e I.8:%J
prion),
2
.re2p107%9,
%
*up%5p (IPSI
[
J prion),
>
8nD1p (IPIN
[
J prion).
5
Gener+ll2, bet+7
tr+n" o? + protein mole$ule run perpen"i$ul+r to t!e +Li o? t!e ?ibril +n" !2"ro'en
bon"in' in u$! tru$ture o$$ur +lon' t!e ?ibril +Li. Et!er mo"el, !o4e@er, nee" to be
$oni"ere" + ome report u''et t!+t t!e p+r+llel in7re'iter tru$tur+l mo"el o?
+m2loi" ?+ile" to eLpl+in eLperiment+l ober@+tion o? t!e "i@erit2 o? tr+in7pe$i?i$
morp!olo'ie o? t!e *up%5 +m2loi" ?ibril.
6
Go to:
&mall %lements Go7ern Prion Aggregation
1!e +bo@e7"e$ribe" t!eme o? tru$tur+l or'+ni<+tion o? ?ibril eem r+t!er $ommon in
t!e ?orm+tion o? +m2loi". *!ort e'ment o? ot!er non7prion +m2loi" protein]+m2loi"7
m,
7,8
w72nu$lein,
9,10
ilet +m2loi" pol2pepti"e ()APP),
11
l2o<2me
12
+n" m27
mi$ro'lobulin
1%
]+re $+p+ble o? ?ormin' +m2loi" ?ibril. )t i re+on+ble to +ume t!+t
t!e n+ture o? +m2loi"o'eni$ re'ion m+2 be "e"u$e" ?rom t!e repe+tin' ?ol"in' moti? in
t!e +m2loi" ?ibril. )n$re+in' e@i"en$e in"i$+te more +n" more t!+t t!e buil"in' blo$0
o? +m2loi" ?ibril +re !ort ?r+'ment o? t!e entire protein eDuen$e. 1!i u''et t!+t
t!e +''re'+tion m+2 be'in 4it! onl2 + !ort e'ment o? t!e entire protein eDuen$e. An2
$!+n'e in en@ironment+l $on"ition t!+t: (1) open + n+ti@e protein $on?orm+tion,
eLpoin' t!i p+rt o? t!e eDuen$e, +n"&or (2) timul+te $on?orm+tion+l $!+n'e to +n
+''re'+tion7prone t+te, $oul" ?+$ilit+te t!e +''re'+tion pro$e. 1!e +bo@e7mentione"
eL+mple upport re$entl2 propoe" +m2loi" tret$! !2pot!ei. 1!e !2pot!ei u''et
t!+t + !i'!l2 +m2loi"o'eni$ !ort +mino +$i" tret$! m+2 tri''er t!e el?7+embl2
pro$e o? + protein into +''re'+te.
1>,15
)nter+$tion bet4een pe$i?i$ protein re'ion
?+$ilit+te t!e neLt tep in t!e ?orm+tion o? + mi?ol"e" $on?orm+tion. 1!ee re'ion +re
0no4n + +''re'+tion o!ot re'ionp,
16,17
4!i$! +re !ort tret$!e o? + prim+r2 protein
eDuen$e.
An ele'+nt +ppro+$! to re$o'ni<e u$! m+ll element o? + prim+r2 eDuen$e t!+t
nu$le+te +n" promote +''re'+tion o? prion protein *up%5 4+ re$entl2 utili<e".
18
An +rr+2
o? o@erl+ppin' pepti"e 20 +mino +$i" in len't! "eri@e" ?rom t!e eDuen$e o? t!e prion
*up%5 4ere $o@+lentl2 +tt+$!e" to + 'l+ li"e. Pepti"e 4ere printe" onto t!e ur?+$e
1012 nm +p+rt ?rom e+$! ot!er, pro@i"in' !i'! reolution +n" retri$tin' el?7
inter+$tion. 1!ee pepti"e +rr+2 4ere in$ub+te" 4it! ?luore$entl2 l+bele" ?ull len't!
5M *up%5. 1!e +$$umul+tion o? ?luore$en$e 4+ ober@e" +?ter 2 !our o? in$ub+tion +t
+ @er2 m+ll et o? imprinte" pepti"e +mino +$i" 9%9 +n" 90120. 1!ee eDuen$e lie
4it!in t!e re'ion 4!i$! 4ere pre@ioul2 i"enti?ie" to be in el?7$ont+$t 4it!in m+ture
?ibril.
19
*u$! + n+no+rr+2 +ppro+$! in"i$+te" t!+t t!ee m+ll re'ion +re not onl2 ite
o? intermole$ul+r $ont+$t in m+ture ?ibril, but t!e2 +lo 'o@ern el?7re$o'nition 4it!in
oluble non7prion $on?ormer 4it! !i'! pe$i?i$it2. 1!ere?ore, m+ll tret$!e o? protein
eDuen$e +re u??i$ient to "ri@e t!e $on@erion o? ?ull7len't! 5M ?rom non7prion t+te
into el?7templ+tin' +m2loi" $on?orm+tion.
18
*ometime + $ompleL inter+$tion +mon'
m+ll re$o'nition element i reDuire" ?or prion prop+'+tion. Por eL+mple, ?our O5 ri$!
"om+in o? 8nD1 $+n in"epen"entl2 tr+nmit t!e prion t+te but +$t $ooper+ti@el2 to
+tt+in t!e ?in+l prion $on?orm+tion.
20
1!e eLiten$e o? tr+nmiion b+rrier +lo i
+??e$te" b2 t!e $ooper+ti@e +$tion o? +ll ?our prion "om+in o? 8nD1.
20
*e@er+l ot!er line
o? e@i"en$e +lo point to $ompleL inter+$tion 4it!in prion protein ?or t!e ?orm+tion o?
tr+in. E!!+!i et +l.
21
re$entl2 reporte" t!+t tr+nient non7n+ti@e inter+$tion outi"e t!e
re$o'nition element +re import+nt in "eterminin' temper+ture7"epen"ent tr+in
$on?orm+tion o? *up%5.
Go to:
"irect !bser7ation of 3ibril Growth
Alt!ou'! $on@in$in' tru$tur+l mo"el o? +m2loi" ?ibril !+@e re$entl2 emer'e", t!e
0no4le"'e o? pre$ie 0ineti$ me$!+nim o? ?ibril ?orm+tion 4oul" 're+tl2 bene?it our
un"ert+n"in' o? t!e prion p!enomenon. 5o@el tool 4!i$! en+ble t!e "ire$t ober@+tion
o? in"i@i"u+l ?ibril 'ro4t! +re import+nt not onl2 ?or obt+inin' ?urt!er ini'!t into t!e
me$!+nim o? protein el?7+o$i+tion but +lo ?or i"enti?2in' $ompoun" t!+t in!ibit
?ibril 'ro4t!. 8e$ent +"@+n$e in in'le mole$ule met!o" o??ere" b2 t!e +tomi$ ?or$e
mi$ro$op2 +n" in'le mole$ule ?luore$en$e mi$ro$op2 +llo4e" t!e monitorin' o?
+''re'+tion +t t!e le@el o? in"i@i"u+l ?ibril pro@i"in' in?orm+tion +bout t!e r+te +n"
"ire$tion o? 'ro4t!.
1!e in'le7?ibril 'ro4t! o? 5M *up%5 4+ eL+mine" uin' tot+l intern+l re?le$tion
?luore$en$e mi$ro$op2 (1)8P).
22
(257l+bele" ee" 4ere +tt+$!e" to + 'l+ li"e @i+
biotin7trept+@i"in lin0+'e. 1!e (2%7l+bele" monomer 5M 4+ +""e" to t!e olution.
1!e +""ition o? in"i@i"u+l (2%7l+bele" mole$ule $oul" be re+"il2 "ete$te" +t t!e en" o?
(257l+bele" ?ibril. .in' u$! +n eLperiment+l etup, 4!ere me+urement $oul" ?ollo4
t!e ?luore$en$e intenitie o? t!e +""ition e@ent, m+"e it poible to "etermine !o4
m+n2 mole$ule +re +""e" "urin' + in'le e@ent. 1!e "+t+ et+bli!e" t!+t t!e ?ibril
'ro4t! pro$ee" @i+ +""ition o? 5M monomer onto ?ibril en", pro@i"in' +""ition+l
e@i"en$e ?or t!e me$!+nim o? ?ibril 'ro4t!. Ho4e@er, u$! eLperiment reDuire"
l+belin' o? protein 4it! "2e mole$ule, +n" t!e intro"u$tion o? t!e l+bel mi'!t inter?ere
4it! +''re'+te ?orm+tion +n"&or me+urement.
Anot!er met!o" !+ been intro"u$e" to monitor t!e ?orm+tion pro$e o? +m2loi" ?ibril
4it!out l+belin' o? + protein mole$ule.
2%
1!e ue o? +m2loi"7?ibril pe$i?i$ "2e 1!io?l+@in
1 (1!1) ?luore$en$e in $ombin+tion 4it! tot+l intern+l re?le$tion ?luore$en$e
mi$ro$op2 (1)8PM) en+ble" + "ire$t ober@+tion o? t!e +m2loi" ?ibril 'ro4t! in re+l
time.
2%25
5o +""ition+l ?luorop!ore l+belin' 4+ reDuire" to @iu+li<e ee"7"epen"ent
+m2loi" ?ibril 'ro4t! o? m72m,
2%
or Am1>0,
2>,25
+t t!e in'le ?ibril le@el.
Anot!er ue?ul tool ?or "ire$t ober@+tion o? +m2loi" ?ibril 'ro4t! 4!i$! !+ been 4i"el2
ue" i APM]+tomi$ ?or$e mi$ro$op2. 1!e m+in +"@+nt+'e o? APM i it +bilit2 to
monitor on'oin' pro$ee un"er @+riou olution $on"ition 4it!out +n2 eLtr+ l+belin'
reDuire". 8e$entl2, APM 4+ u$$e?ull2 ue" to monitor t!e el?7+embl2 o? e@er+l
+m2loi"o'eni$ protein,
26,27
in$lu"in' +m2lin +n" +m2loi"7bet+.
28,29
An +embl2 o?
in"i@i"u+l ?ibril ?orme" b2 +m2loi" bet+725%5 4+ tu"ie" b2 + mo"i?ie" +ppli$+tion o?
t!e +tomi$ ?or$e mi$ro$op2, $+nnin' ?or$e 02mo'r+p!2.
%0
1!i met!o" elimin+te" t!e
nee" to $+n t!e 4!ole im+'e b2 $+nnin' ?ibril onl2. *u$! +n impro@ement i'ni?i$+ntl2
in$re+e" t!e tempor+l reolution 4it! 4!i$! t!e ober@+tion o? in'le ?ibril elon'+tion
pro$e i me+ure". .in' t!i met!o", 6ellerm+2er et +l.
%0
!+@e "etermine" t!+t t!e
+embl2 o? t!e ?ibril i pol+ri<e" +n" "i$ontinuou. 1!e +m2loi" +embl2 pro$ee"e"
@i+ r+pi" burt o? 'ro4t! t!+t eLten"e" t!e ?ibril b2 7 nm or it inte'er multiple.
%0
1!e
'ro4t! p!+e 4ere ?ollo4e" b2 p+ue in + tep4ie m+nner, u''etin' + ?lu$tu+tion o?
+m2loi" t+te in 4!i$! 'ro4t! m+2 be eit!er permitte" or in!ibite".
A in'le ?iber 'ro4t! ++2 4+ ue" to eL+mine t!e !etero'eneit2 o? +m2loi" ?ibril
?orme" b2 t!e 2e+t *up%5 prion protein. 1!i ++2 ue" t4o @+ri+nt o? t!e *up%5 t!+t
4ere "i??erenti+ll2 l+bele" +n" "itin'ui!e" b2 APM. 1!e t4o @+ri+nt "i??ere" in t!eir
+bilit2 to bin" +n +ntibo"2, pro@i"in' + me+n o? i"enti?i$+tion o? one t2pe o? t!e protein
b2 APM be$+ue bin"in' t!e +ntibo"2 in$re+e t!i$0ne o? t!e ?iber %7?ol". 1!i tu"2
?oun" t!+t *up%5 pont+neoul2 ?orm multiple +n" "itin$t ?ibril t2pe. 1!ee t2pe
"i??er b2 t!e "e'ree o? pol+rit2 +n" o@er+ll 'ro4t! r+te, u''etin' + 're+t @+ri+tion in
propertie o? t!e ?ibril. 1!e ober@e" "i@erit2 eem to be 4ell7uite" to +$$ount ?or t!e
r+n'e o? prion tr+in p!enot2pe.
%1
Go to:
Polymorphism and Prion &trains
Am2loi" ?ibril 'ener+ll2 eL!ibit imil+r +ppe+r+n$e in + ?orm o? elon'+te", unbr+n$!e"
tru$ture. *e@er+l unrel+te" protein u$! + inulin, +m2loi" bet+ +n" +m2lin $+n ?orm
+lmot i"enti$+l morp!olo'ie. A''re'+te" prion protein +lo eL!ibit imil+r +m2loi"
?ibril +ppe+r+n$e. #epite t!e 'ener+l imil+rit2 o? +''re'+te" pe$ie, o?ten + miLture o?
?ibril 4it! @+riou morp!olo'ie i ?orme". Moreo@er, ?ibril o? t!e +me pol2pepti"e
eDuen$e $+n ?orm "itin$t morp!olo'ie eL!ibitin' + 're+t 4e+lt! o? pol2morp!im.
3igure 1 !o4 APM im+'e o? ?ibril ?orme" b2 t!e (G55OO5Y pepti"e in "i??erent
en@ironment+l $on"ition. *imple @+ri+tion in t!e en@ironment u$! + pH +n" ioni$
tren't! o? olution, temper+ture +n" me$!+ni$+l tre (?or eL+mple, +'it+tion) $+n reult
in t!e ?orm+tion o? ?ibril 4it! "i??erent $!+r+$teriti$. Moreo@er, prion protein +re
$+p+ble o? ?ormin' +''re'+te 4!i$! "i??er in t!eir p+ttern o? prote+e reit+n$e +n"
tr+nmiibilit2. 1!e "i??eren$e in t!ee propertie o? +''re'+te i 'ener+ll2 re?erre" to
+ prion tr+in. )n tr+nmiible pon'i?orm en$ep!+lop+t!ie, "itin$t p!enot2pe o? +
"ie+e $orrepon" to "i??erent prion tr+in.
%2
Pi'ure 1
*$!eme illutr+tin' t!+t + protein mole$ule $+n +"opt e@er+l $on?orm+tion+l t+te 4!i$!
m+2 reult in +''re'+te o? "i??erent morp!olo'ie. APM im+'e o? (G55OO5Y
pepti"e ?rom *up%5 2e+t prion protein +''re'+te" 4it! t!e ?orm+tion o? ?ibril o?
"itin$t )))
1!e p!enomenon o? prion tr+in implie t!+t t!ere eLit +n enemble o? "itin$t
prop+'+tin' $on?orm+tion ?or + in'le pol2pepti"e eDuen$e. 1!ere?ore, +''re'+tion o?
pol2pepti"e mi'!t pro"u$e e@er+l "itin$t pol2morp! "epen"in' on initi+l mi?ol"e"
$on?orm+tion. 1!e "2n+mi$ n+ture o? t!e $on?orm+tion+l p+$e, t!e $ompleLit2 o?
rel+tion!ip bet4een tr+in +n" t!e potenti+l to 'ener+te + l+r'e number o? ne4 prion
tr+in poe + $riti$+l nee" ?or +""rein' t!ee iue. 1!e 're+t 4e+lt! o?
pol2morp!im +n" "i@erit2 o? prion tr+in preent + eriou ri0 ?or publi$ !e+lt!.
%%
)n"i@i"u+l ?ibril +re 'ener+ll2 $oni"ere" to be tru$tur+ll2 uni?orm, m+int+inin' t!e
+me tru$ture o@er t!e len't! o? t!e ?ibril. )t i belie@e" t!+t t!e morp!olo'2 +n"
tru$ture o? pre?orme" ee" i prop+'+te" in + templ+te7li0e m+nner, p+in' t!e
$!+r+$teriti$ o? templ+te]morp!olo'2, tru$ture +n" in?e$ti@it2]to t!e neLt
'ener+tion o? +''re'+te.
%>%6
*u$! !erit+bilit2 i o tron' t!+t ee" prop+'+te t!eir
$!+r+$teriti$ e@en 4!en $on"ition +re $!+n'e" to ?+@or "i??erent $on?orm+tion+l
t+te.
%7
8e$ent report, !o4e@er, u''et t!+t ?ibrill+r tru$ture +re $ompoe" o? protein
mole$ule t!+t !+@e "i??erent e$on"+r2 tru$ture.
%8,%9
A $riti$+l nee" ?or i"enti?2in'
(probin') t!e $on?orm+tion 4it!in !etero'eneou +mple !+ been re$entl2
!i'!li'!te".
%9
)t i be$omin' $le+r t!+t t!ere i + $oeLiten$e o? multiple tr+in or
ubt2pe o? t!e "ie+e7rel+te" protein in +''re'+te. *u$! $on?orm+tion+l !etero'eneit2
m+2 reult in o@+riou "ie+e.p
A no@el immuno$on?orm+tion+l ++2 (or "u+l $olor ++2) b+e" on pe$i?i$ +ntibo"ie
l+bele" 4it! "i??erent "2e !+ been utili<e" to re@e+l tru$tur+l !etero'eneit2 o? PrP
prion protein 4it!in + in'le ?ibril.
%9
1!i tu"2 !o4e" t!e eLiten$e o? t!e
$on?orm+tion+l !etero'eneit2 +$ro t!e popul+tion o? ?ibril + 4ell + 4it!in in"i@i"u+l
?ibril.
8e$ent ^7r+2 $r2t+llo'r+p!2 +n" 5M8 tru$tur+l tu"ie emer'e" to u''et tron'l2
t!e ori'in o? pol2morp!i$ @+ri+tion. Multiple l+2er o? bet+7!eet +re $loel2 p+$0e" to
$re+te +m2loi" tru$ture. #i??eren$e in t!e p+$0in' o? t!ee bet+7!eet, ori'in+tin'
?rom i"e7$!+in p+$0in', re'iter or topolo'2 o? bet+7!eet, m+2 eLpl+in morp!olo'i$+l
@+ri+nt o? ?ibrill+r tru$ture. *oli"7t+te 5M8 tu"ie $le+rl2 !o4e" t!e $oeLiten$e o?
t!ree "itin$t $on?orm+tion o? t!e G55OO5Y pepti"e 4it!in + in'le ?ibril.
%8
#i??erent
p+$0in' +rr+n'ement o? pepti"e 4it!in + ?ibril 4ere propoe" to be reponible ?or t!e
ober@e" "i??eren$e in 5M8 $!emi$+l !i?t. 1!ee $oeLitin' $on?orm+tion "i??er b2
t!e "e'ree o? lo$+l e$on"+r2 tru$ture (+lp!+ !eli$+l @eru bet+ !eet).
%8
8e$ent
$r2t+llo'r+p!i$ tu"ie !+@e i"enti?ie" e@er+l (8) $l+e o? o7$+lle" teri$ <ipper.
9

#epite t!e ?un"+ment+l imil+ritie in t!e tru$ture 4it! eLten"e" protein tr+n" t!+t +re
perpen"i$ul+r to t!e +Li o? bet+ !eet, t!ee $l+e @+r2 in t!e b+i$ teri$ <ipper
tru$ture. *u$! @+ri+tion in@ol@e m+inl2 orient+tion o? pepti"e +n" bet+7!eet 4it!
repe$t to e+$! ot!er. )t 4+ ?oun" t!+t ome pepti"e 4ere $+p+ble o? ?ormin' "i??erent
pol2morp! 4it! re'+r" to t!eir b+i$ teri$ <ipper tru$ture, o??erin' + poible
eLpl+n+tion ?or +m2loi" pol2morp!im +n" prion tr+in.
9
#ue to t!e "i??i$ult2 o? "eterminin' t!e tru$ture o? +m2loi" +n" t!e potenti+l ?or
tru$tur+l !etero'eneit2 4it!in + in'le ?ibril, one +ppre$i+te t!e "e@elopment o? no@el
met!o" t!+t $oul" pro@i"e in?orm+tion +bout t!e morp!olo'2 o? +''re'+te + 4ell +
t!eir un"erl2in' $on?orm+tion+l "i??eren$e. 1!ee met!o" +re $urrentl2 emer'in' + +
$ombin+tion o? APM +n" @ibr+tion+l pe$tro$op2 (in?r+re" +borption or 8+m+n
pe$tro$op2) $+p+ble o? re$o'ni<in' t!e e$on"+r2 tru$ture o? protein. )8 +n" 8+m+n
$+tterin' !+@e re$entl2 ?oun" + 4i"e +ppli$+tion in $!+r+$teri<+tion o? +m2loi".
>0>%
Ene
o? t!e bi''et +"@+nt+'e o? u$! $ombine" met!o" i t!+t @ibr+tion+l propertie $+n be
ober@e" imult+neoul2 4it! t!e topo'r+p!i$ im+'e. An +""ition+l +"@+nt+'e i t!+t t!e
probin' o? !etero'eneou +mple i poible.
Ene re$ent illutr+ti@e eL+mple i + $ombin+tion o? APM +n" ne+r7?iel" in?r+re"
mi$ro$op2.
>>,>5
Aperturele ne+r7?iel" $+nnin' in?r+re" mi$ro$op2 (A5*)M) 4+
utili<e" to tu"2 t!e morp!olo'2 +n" e$on"+r2 tru$ture o? in"i@i"u+l +m2loi" ?ibril o?
bet+72 mi$ro'lobulin. (ouplin' ne+r7?iel" in?r+re" pe$tro$op2 4it! APM +llo4e" t!e
$orrel+tion o? ?ibril morp!olo'2 +n" un"erl2in' e$on"+r2 tru$ture. )t 4+ ober@e"
t!+t t!e +mple eL!ibite" + !etero'eneou popul+tion o? ?ibril: ome ?ibril !+" p+r+llel
+n" ome +nti7p+r+llel bet+ !eet +rr+n'ement.
Ene "i+"@+nt+'e o? A*5)M i it limit+tion to onl2 + ?e4 ele$te" 4+@elen't!. 1!i $+n
2iel" to mile+"in' interpret+tion i? +n im+'e $ontr+t o? onl2 one or t4o ele$te"
4+@elen't! i $oni"ere". E@erl+ppin' ?e+ture o? uneLpe$te" b+n", li'!t b+n" 4it!
$!+n'e or !i?t $+n t!ere?ore e+il2 poil +n interpret+tion. )n or"er to o@er$ome t!i
!ort$omin', + ?ull pe$trum i reDuire", but t!i i onl2 poible 4it! op!iti$+te"
eDuipment +t 2n$!rotron our$e.
A rel+te" +ppro+$! t!+t +llo4 tu"ie o? t!e e$on"+r2 tru$ture o? ?ibril i re+li<e" b2
tip7en!+n$e" 8+m+n $+tterin' (1:8*).
>6>8
)n 1:8*, +n APM or *1M ($+nnin'
tunnelin' mi$ro$ope) i $ombine" 4it! + t+n"+r" 8+m+n mi$ro$ope in or"er to eL$ee"
t!e "i??r+$tion limit +n" to in$re+e t!e eniti@it2 o? $on@ention+l 8+m+n pe$tro$op2.
1!i i re+li<e" b2 +tt+$!in' + in'le il@er or 'ol" n+nop+rti$le to t!e +peL o? +n APM tip
or b2 utili<in' +n et$!e" 4ire. *imil+r to t!e A*5)M +ppro+$!, @ibr+tion+l mo"e o?
mole$ule un"er t!e tip eLperien$e + i'n+l en!+n$ement o? e@er+l or"er o? m+'nitu"e.
Por +n o@er@ie4, ee re?.
>9
. Gi@en t!+t 1:8* i + $+tterin' t2pe o? pe$tro$op2, + in'le
eL$it+tion ?reDuen$2 2iel" + ?ull pe$trum. Hen$e, o@erl+ppin' b+n" o? uneLpe$te"
$ompoun" $+n be "itin'ui!e" e+il2 b2 multi@+ri+te t+titi$, ?or int+n$e. 1!i
ren"er 1:8* + !i'!l2 eniti@e met!o", 4it! e@en in'le7mole$ule eniti@it2.
50,51

*imult+neoul2 to pe$tr+ +$Duiition 4it! + l+ter+l reolution "etermine" b2 t!e
n+nop+rti$le "imenion, t!e topo'r+p!2 o? t!e +mple +lo i m+ppe" 4it! + p+ti+l
reolution $omp+r+ble to t+n"+r" APM te$!nolo'2. Purt!ermore, 1:8* oper+te l+bel7
?ree +n" non7"etru$ti@e, 4!i$! me+n t!+t t!e +mple $+n be ue" ?or + ubeDuent
+n+l2i.
3igure 6A !o4 + t2pi$+l 1:8* etup. 1!ree pe$tr+ o? + in'le +m2loi" ?ibril ?orme"
?rom + (G55OO5Y pepti"e (?r+'ment o? *up%5 2e+t prion protein) +t pH 5.6 +re
ele$te" +n" !o4n in 3igure 6(. 1!e pe$tr+ 4ere re$or"e" +t eDui"it+nt (7 nm)
poition perpen"i$ul+r to t!e m+in ?ibril +Li. *in$e t!e pepti"e !+" onl2 + !ort
eDuen$e o? ei'!t +mino +$i", +ll pe$tr+ in 3igure 6( +re imil+r. 1!e pe$i?i$ poition
o? t!e +mi"e ) +n" +mi"e ))) b+n" pro@i"e e@i"en$e o? + m7!eet tru$ture t!+t i t+ble in
t!i +re+ o? t!e ?ibril. Por ?ibril 4it! @+r2in' e$on"+r2 tru$ture, 1:8* en+ble t!e
pre$ie lo$+li<+tion +n" +i'nment o? "i??erent $on?orm+tion.
Pi'ure 2
(A) *0et$! o? + b+$0 re?le$tion 1:8* etup, (/) 1:8* pe$tr+ o? + ?ibril ?orme" b2
(G55OO5Y pepti"e ?rom *up%5 2e+t prion protein on +"M+$ent point ep+r+te" b2 7
nm.
Prom pre@iou 1:8* tu"ie on +mino +$i" it i 0no4n t!+t "itin$t +mino +$i" +re
"itin'ui!+ble b2 pe$i?i$ pe$tr+l ?e+ture.
52,5%
)n t!e preent eLperiment, +n +i'nment
o? $2teine (() +n" t2roine (Y) i poible +n" $orrepon"in' i'n+l +re m+r0e" in t!e
pe$trum. *u$! +n +i'nment $+n "eli@er @+lu+ble in?orm+tion i? t!e ?ibril 4+ 'ener+te"
?rom @+riou or e@en un0no4n pepti"e.
Go to:
The Nature of an Infectious Agent
1!e rel+tion!ip bet4een prion prop+'+tion p!enomenon +n" t!e ?orm+tion o? +m2loi"
?ibril i poorl2 un"ertoo". Mot 0no4n +m2loi"7?ormin' protein +re not prion +n"
e@en +m2loi" o? prion protein +re not +l4+2 tr+nmiible.
5>56
1!ere i till + poor
un"ert+n"in' o? 4!2 $!+n'e in t!e $on?orm+tion o? mi?o"e" protein $+n +lter t!eir
p!2iolo'i$+l e??e$t. 8e$entl2 propoe" !2pot!ei o? o?r+n'ibilt2p o? +m2loi" ?ibril
o??ere" +n eLpl+n+tion t!+t mi'!t $l+ri?2 t!i $ompli$+te" iue.
57
1!e me$!+ni$+l
propertie o? +m2loi" +n" +m2loi"N propenit2 to bre+0, 'ener+tin' ne4 ee", eem to
"e?ine t!eir p!2iolo'i$+l imp+$t.
57
1+n+0+ et +l.
57
loo0e" +t t!e "i??eren$e in t!ree
$on?orm+tion (tr+in) o? prion protein *up%5 ?orme" +t >n( (*$>), %7n( (*$%7) +n"
room temper+ture (*(*). 1!ee t!ree prion tr+in "i??er b2 t!eir pol2meri<+tion r+te
+n" $+ue "itin$t $olor p!enot2pe in t!e A#: $olor ++2. An APM7b+e" in'le7?iber
'ro4t! ++2 4+ ue" to me+ure ?iber 'ro4t! r+te ?or t!ee t!ree "itin$t
$on?orm+tion. )t 4+ ?oun" t!+t "epite t!e ?+$t t!+t *$> le+" to t!e tron'et tr+in
p!enot2pe, it !+ t!e lo4et intrini$ ?iber 'ro4t! o? t!e t!ree $on?ormer. 1!e p!2i$+l
tren't! o? t!e $on?ormer turne" out to be "i??erent, too. 1!e lo4er 'ro4t! o? *$> i
+$$omp+nie" b2 + 're+ter "e'ree o? ?r+'ment+tion upon tirrin'. APM im+'in' re@e+le"
t!+t tirrin' !+ttere" *$> +m2loi" into m+n2 m+ll ?ibril (le t!+n 100 nm). *u$!
tre+tment +lo in$re+e" ee"in' e??i$ien$2 $onitent 4it! l+r'er number o? ?ibril en".
1!e @+ri+bilit2 in t!e brittlene o? t!e ?ibril 4+ propoe" to repreent + m+Mor
me$!+nim b2 4!i$! t!e tren't! o? prion tr+in p!enot2pe i "etermine" b2
$on?orm+tion+l t+te o? t!e protein.
57
)t +ppe+r t!+t, in @i@o, t!e Hp10> $!+perone !elp
to ?r+'ment ?ibril o? *up%5 prion protein, +n" it i +lo reponible ?or "i+''re'+tin'
l+r'e protein "epoit. 1!i $!+perone m+2 pl+2 +n import+nt role in prop+'+tion o? prion
be$+ue "eletion o? Hp10> !+ been "emontr+te" to elimin+te t!e in?e$ti@it2 o? prion
(re@ie4e" in re?.
58
).
8e$ent tu"ie et+bli!e" + tron' $orrel+tion bet4een t!e in$ub+tion perio" o? prion
"ie+e +n" $on?orm+tion+l t+bilit2 o? 2nt!eti$ prion.
59,60
1!e $on?orm+tion+l t+bilit2 o?
+ 2nt!eti$ prion ?orme" ?rom + ?ull7len't! m+mm+li+n prion protein 4+ +lo ?oun" to
$orrel+te 4it! t!e m+llet poible i<e o? t!e ?r+'ment.
61
3e t+ble $on?orm+tion
pro"u$e" m+ller pie$e o? ?ibril upon ?r+'ment+tion, pro@i"in' +""ition+l e@i"en$e t!+t
?r+'ment+tion m+2 be import+nt in tr+nmiibilit2 o? prion +''re'+te +n" prion "ie+e
"e@elopment. *un et +l.
61
+lo !o4e" t!+t w/7$r2t+llin, + !e+t !o$0 protein (Hp), i
$+p+ble o? ?r+'mentin' rPrP ?ibril.
61
An +ltern+ti@e !2pot!ei ?or t!e ori'in o? ?ibril b2
t!eir inter+$tion 4it! + ur?+$e o? $ellul+r membr+ne !+ been propoe".
61
Protein +''re'+tion i + $ompleL pro$e 4!i$! pro$ee" @i+ m+n2 interme"i+te t+te,
in$lu"in' oli'omer, proto?ibril +n" ?ibril. 1!ere i in$re+in' e@i"en$e t!+t t!e en"
pro"u$t o? +''re'+tion]t!e ?orm+tion o? ?ibril +n" bi' +''re'+te]i not t!e m+in
$+ue o? t!e "ie+e. 1!ere eLit +n un$ert+int2 +bout 4!+t pe$ie in t!i $ompleL
+''re'+tion p+t!4+2 +re reponible ?or t!i toLi$it2. Alt!ou'! t!e in?e$ti@it2 o? prion i
+o$i+te" 4it! + 4i"e r+n'e o? +''re'+te" t+te, m+ll oli'omer o? +''re'+te" prion
protein !+@e been u''ete" + minim+l in?e$tiou p+rti$le. A re$ent tu"2 re@e+le" t!+t
t!e in?e$ti@it2 o? PrP i t!e 're+tet ?or p+rti$le 1727 nm in i<e, $orrepon"in' to %00
600 0#+.
62
1!ee oli'omeri$ p+rti$le !oul" $onit o? 1> to 28 prion monomer. 1!e
in?e$ti@it2 i "e$re+e" ?or l+r'er +''re'+te +n" @irtu+ll2 +bent ?or oli'omeri$ ?r+$tion
o? K5 mole$ule.
62
1!e +bo@e7"e$ribe" eLperiment+l ober@+tion upport e@en more tron'l2 t!e ne4
emer'in' @ie4 t!+t in?e$tiou +n" toLi$ pe$ie o? prion mi'!t !+@e "i??erent i"entitie
1

4it! "itin$t biop!2i$+l propertie.
55
Alt!ou'! +m2loi" ?orm o? PrP +re in?e$tiou, t!e2
mi'!t not be toLi$.
55
An in$re+in'l2 +$$umul+tin' bo"2 o? e@i"en$e u''et t!+t
oli'omeri$ +emblie o? +m2loi" protein +re toLi$ pe$ie,
6%67
4!ile l+r'e +''re'+te
+n" ?ibril +re r+t!er inert or e@en prote$ti@e.
68
(!+r+$teri<+tion o? oli'omeri$ pe$ie 4it! $on@ention+l, enemble b+e" met!o" i
$!+llen'in' "ue to "2n+mi$ +n" tr+nient n+ture o? oli'omer. *in'le mole$ule met!o"
$+n pro@i"e uniDue in?orm+tion on t!e tru$ture, ener'eti$ +n" "2n+mi$ o? interme"i+te
tr+nient pe$ie ?orme" "urin' initi+l t+'e o? +''re'+tion. 8e$entl2, + "u+l7$olor,
in'le7mole$ule ?luore$en$e te$!niDue !+ been utili<e" to loo0 +t t!e e+rl2 t+'e o?
+''re'+tion o? t!e *H% "om+in o? P)% 0in+e "urin' +''re'+tion l+' +n" 'ro4t! p!+e.
69
1!e tu"2 ?oun" t!+t t!e oli'omeri$ pe$ie ?orme" in t!e +''re'+tion re+$tion $omprie
+ !etero'eneou enemble o? oli'omer 4it! t!e me"i+n i<e o? %8 S 10 mole$ule.
)nteretin'l2, t!i t+'e o? +''re'+tion re+$tion !+ been pre@ioul2 ?oun" to be
m+Lim+ll2 $2totoLi$. 1!e inno@+ti@e $!+r+$ter o? t!e tu"2 i t!e +ppli$+tion o? 1((#]
t4o7$olor $oin$i"en$e "ete$tion]to tu"2 t!e protein el?7+embl2 pro$e. Protein
mole$ule 4ere l+bele" 4it! t4o "i??erent "2e (AleL+ Pluor >88 +n" AleL+ Pluor 6>7)
t!+t $+n be "ete$te" ep+r+tel2. 1!e ?orm+tion o? oli'omer pro$ee"e" @i+ +embl2 o?
protein in$orpor+tin' bot! t2pe o? "2e into +''re'+te" pe$ie. 1!e preen$e o?
oli'omer i m+ni?ete" b2 imult+neou ?luore$en$e burt in bot! re" (AleL+ Pluor
6>7) +n" blue (AleL+ Pluor >88) $!+nnel. 1!i +llo4e" reol@in' t!e in"i@i"u+l pe$ie
preent "urin' t!e initi+l t+'e o? +''re'+tion pro$e. )nteretin'l2, t!e tu"2 +lo ?oun"
t!+t t!e t+bilit2 o? oli'omeri$ pe$ie in$re+e 4it! time 4!ile t!e i<e o? oli'omer
t+2 @irtu+ll2 t!e +me. Ene poible eLpl+n+tion ?or t!i e??e$t i t!+t t!e intern+l
$on?orm+tion+l reor'+ni<+tion o? "ior"ere" oli'omer le+" to en!+n$e" t+bilit2 "urin'
?ibril ?orm+tion.
69
*u$! + $on$luion i in t!e line 4it! pre@ioul2 propoe" nu$le+te"
$on?orm+tion+l $on@erion (5(() mo"el ?or *up%5.
70
)mport+ntl2, + re$ent tu"2 o? m7
l+$to'lobulin +''re'+tion propoe" + imil+r me$!+nim o? ?ibril ?orm+tion.
69
Eli'omer
!oul" un"er'o + $riti$+l $on?orm+tion+l $!+n'e to be$ome nu$le+tin' oli'omer t!+t
ee" +m2loi" ?orm+tion. 1!e i<e o? u$! nu$le+tin' oli'omer !+ been propoe" to be
+ m+ll + 16 mole$ule.
71
1!e +bo@e7"e$ribe" tu"ie emp!+i<e t!e +"@+nt+'e o? n+notool to un"ert+n" t!e
me$!+nim un"erl2in' "2n+mi$ e+rl2 e@ent o? protein el?7+o$i+tion t!+t in@ol@e
?orm+tion o? tr+nient oli'omeri$ pe$ie. A""ition+ll2, in'le7mole$ule met!o" +@oi"
+@er+'in' o? in?orm+tion o@er t!e enemble, +""rein' u$! import+nt iue + t!e
!etero'eneit2 o? t!e ?orme" pe$ie.
Go to:
&pecies (arrier
1!e limite" +bilit2 to tr+nmit t!e in?e$tiou t+te bet4een prion protein o? "i??erent
pe$ie i re?erre" to + ope$ie b+rrier.p 1!e mole$ul+r b+i o? t!i pro$e i $urrentl2
poorl2 un"ertoo". Ho4e@er, it i !2pot!ei<e" t!+t t!e pe$ie b+rrier i $ontrolle" b2
t!e mi?ol"in' o? t!e prion protein +n" it $on?orm+tion+l propertie.
72,7%
5e@ert!ele, t!e
pe$ie b+rrier i belie@e" to be $loel2 rel+te" to t!e pe$i?i$it2 o? inter+$tion bet4een
t!e templ+te +n" t!e ubtr+te.
Amon' ot!er ?+$tor, prim+r2 tru$ture (+mino +$i" eDuen$e) pl+2 + $riti$+l role in
"e?inin' t!e +bilit2 o? prion to prop+'+te t!rou'! + pe$ie b+rrier. )t 'ener+ll2 !+ been
belie@e" t!+t t!e e??i$ien$2 o? $ro7pe$ie prion tr+nmiion i "ire$tl2 rel+te" to t!e
"e'ree o? !omolo'2 in t!e prim+r2 eDuen$e o? prion ?or t4o pe$ie.
7>
*ome report
in"i$+te, !o4e@er, t!+t interpe$ie tr+nmiion i + mu$! more $ompleL p!enomenon
t!+n imple tr+nmiion bet4een $loel2 rel+te" pe$ie. #epen"in' on t!e pe$ie +n"
t!e "ire$tion o? prion tr+nmiion, t!e pe$ie b+rrier o? prion in?e$tion @+rie
i'ni?i$+ntl2. Por eL+mple, ?ibrilli<+tion o? moue prion protein PrP (2%1>>) $+n be
ee"e" 4it! ?ibril o? bot! moue prion +n" !+mter prion protein 4!i$! !+@e 9>U
!omolo'2 in eDuen$e.
7%
En t!e ot!er !+n", t!e +''re'+tion o? !+mter prion protein
$oul" onl2 be ee"e" b2 !+mter +m2loi" ?ibril but not moue. 8em+r0+bl2, moue
+m2loi" ?ibril 4!i$! 4ere ee"e" b2 !+mter +m2loi" ?ibril $oul" ee" ?ibrilli<+tion o?
t!e !+mter monomer. Alter+tion o? p!enot2pi$ p+ttern 4+ +lo ober@e" in t!e $ro7
pe$ie re@ere tr+nmiion o? *up%5 protein o? S'##3'ro(/#&% #&r&."%"'& IPSI
[
J to S+
p'r'0oM*% or S+ -'/'n*% +n" b+$0 to S+ #&r&."%"'&.
75
A tron' @+ri+nt o? S+ #&r&."%"'&
prion 4+ re@erible 4!en prop+'+te" @i+ + protein 4it! S+ p'r'0oM*% prion "om+in, but
t!e tr+nmiion @i+ S+ -'/'n*% prion "om+in +ltere" t!e p!enot2pe o? iol+te" IPSI
[
J,
reultin' in + 4e+0er tr+in.
75
Pre@iou tu"ie "emontr+te" t!+t + in'le +mino +$i" ubtitution 4it!in + !ort
eDuen$e tret$!, lo$+te" in + prion "om+in, "r+ti$+ll2 $!+n'e p+ttern o? $ro7pe$ie
prion $on@erion.
75
A ne4 i"e+ !+ emer'e", u''etin' t!+t + prim+r2 tru$ture +lter t!e pe$trum o?
pre?erre" $on?orm+tion ?or + protein, t!ereb2 +??e$tin' tr+nmiion pe$i?i$it2.
%5
1!e
r+n'e o? u$! pre?erre" $on?orm+tion mi'!t be eniti@e not onl2 to + prim+r2 eDuen$e
but +lo to en@ironment+l $on"ition. )t eem t!+t t!e eLiten$e o? prion tr+in +n"
ope$ie b+rrierp +re $loel2 rel+te" p!enomen+. A "itin$t tr+in $on?orm+tion o? *up%5
!+ re$entl2 been i"enti?ie" t!+t i $+p+ble o? tr+nmiion ?rom S+ #&r&."%"'& to t!e
!i'!l2 "i@er'ent C'n0"0' '!-"#'n%.
%5
)nteretin'l2, t!e ne4l2 'ener+te" prion tr+in $oul"
be tr+nmitte" b+$0 to 2e+t, timul+tin' +''re'+tion o? *up%5 in S+ #&r&."%"'&. 1!ee
reult u''et t!+t e@en tron' pe$ie b+rrier (onl2 >0U imil+rit2 in eDuen$e o?
prion "om+in bet4een *$ +n" (+) $+n be bri"'e" +n" t!ere?ore no pe$ie b+rrier $+n be
$oni"ere" +bolute.
%5
Gener+ll2, t!e ee"in' pro$e i @ie4e" + prop+'+tion o? morp!olo'2 +n" t!e tru$ture
o? pre?orme" ee". 1!i pro$e i belie@e" to o@er$ome eDuen$e7 +n"&or $on"ition7
b+e" tru$tur+l pre?eren$e, reultin' in ?ibril t!+t in!erit t!e $!+r+$teriti$ o? t!e
templ+te (re@ie4e" in re?.
7>
). En + imil+r note, tr+nmiion t!rou'! + $ro7pe$ie
b+rrier i $oni"ere" to pro"u$e t!e +me tr+in o? t!e prion. Ho4e@er, tr+in 4it$!in'
!+ been ober@e" ?or e@er+l prion 2tem. 8e$ent tu"ie illutr+te" t!+t +n +m2loi"
$+n +$$ommo"+te + i'ni?i$+nt $on?orm+tion+l 4it$! 4it!in + in'le ?ibril.
%7
*u$! +
$on?orm+tion+l 4it$! 4+ !o4n to o$$ur 4!en t!e +mino +$i" eDuen$e o? t!e
pre$uror "i" not m+t$! t!e eDuen$e o? t!e templ+te. 1!e ?ibril ?orm+tion o? moue PrP
4+ ee"e" 4it! pre?orme" ?ibril o? !+mter PrP. #epite t!e mim+t$! in +mino +$i"
eDuen$e, in"i@i"u+l ?ibril 4ere +ble to re$ruit t!e !eterolo'ou re$ombin+nt prion
protein. 1!e elon'+tion o? t!e ?ibril in t!i $+e pro$ee"e" t!rou'! +n +"+pt+tion o? +
"i??erent $on?orm+tion+l t+te.
%7
8e$ent report +lo +"" to t!e $ompleLit2 o? t!e pe$ie b+rrier p!enomenon b2 !o4in'
t!+t t!e l+$0 o? prion $o+''re'+tion ?or t4o pe$ie "oe not $orrel+te 4it! "e$re+e"
$ro7pe$ie prion tr+nmiion.
76
1!i ober@+tion, t!ere?ore, u''et t!+t prion
tr+nmiion pe$i?i$it2 i $ontrolle" +t t!e le@el o? $on?orm+tion+l tr+nition r+t!er t!+n
$o+''re'+tion.
Go to:
*olecular *echanisms of Protein *isfolding
1!ere i +n in$re+in' +mount o? e@i"en$e !o4in' t!+t m+n2 protein (i? not +ll) !+@e
t!e +bilit2 to ?orm ?ibril un"er +ppropri+te $on"ition.
77,78
)t eem t!+t +lt!ou'! t!e2 +re
@er2 "i@ere in len't!, ?un$tion +n" lo$+tion in t!e or'+nim, +''re'+te +n" ?ibril !+@e
imil+r morp!olo'ie +n" $ommon propertie. #epite t!e "i@erit2 o? tru$tur+l
pe$uli+ritie o? +''re'+tion pre$uror, t!e2 m+2 be ri$! in m7!eet, w7!eli$e or e@en
n+ti@el2 un?ol"e" protein; t!e +''re'+tion i +$$omp+nie" b2 "et+bili<+tion o? t!e
n+ti@e tru$ture +n" imult+neou ?orm+tion o? m7!eet. m7!eet +re ?orme" bet4een
+ltern+tin' pepti"e tr+n" 4!i$! run perpen"i$ul+r to t!e lon' +Li o? t!e ?ibril
(re@ie4e" in re?.
79
). 1!ee tru$ture m+2 be t+bili<e" eit!er b2 t!e net4or0 o? !2"ro'en
bon"in' bet4een bot! m+in7$!+in +mi"e +n" b2 i"e $!+in rei"ue, 4!i$! turn t!em
into o7$+lle" opol+r <ipperp
80
or b2 !2"rop!obi$ inter+$tion.
81
)t !+ be$ome $ert+in
t!+t t!e +''re'+tion pro$e +n" m7!eet +$Duiition +re $on$erte" e@ent.
82
1!e
+''re'+tion in"u$e" b2 t!e ?orm+tion o? m7!eet7ri$! tru$ture i + uni@er+l
p!enomenon, not retri$te" to + pe$i+l $+te'or2 o? protein. 1!i u''et t!+t $ommon
mole$ul+r me$!+nim mot li0el2 un"erlie t!e +''re'+tion o? @+riou protein into
!i'!l2 or"ere" ?ibrill+r +''re'+te.
8%85
A$$or"in' to mole$ul+r "2n+mi$ (M#) imul+tion, it !+ been u''ete" t!+t t!e
rel+ti@e t+bilit2 o? + monomerN bet+7prone t+te "etermine t!e ?ibrillo'enei o? +
pepti"e.
86
)n$re+in' rel+ti@e t+bilit2 o? bet+7prone t+te reult in $!+n'in' t!e
+''re'+tion p+ttern ?orm "ior"ere" +''re'+tion to ?ibril ?orm+tion, 4it! on7p+t!4+2
interme"i+te +n" ?in+ll2 to ?ibrillo'enei 4it!out +n2 interme"i+te.
Atomi$ ?or$e mi$ro$op2 (APM) 4+ +lo intrument+l in elu$i"+tin' t!e mole$ul+r
ori'in o? ?ibril propertie b2 pro@i"in' ini'!t into 4!+t "etermine u$! m+teri+l + +n
+m2loi" ?ibril.
87
*e@er+l pepti"e 4!i$! re+"il2 ?orm +m2loi" ?ibril 4it! lo4 eDuen$e
imil+rit2 4ere +n+l2<e" in term o? ben"in' ri'i"it2 o? t!e ?orme" ?ibril. 1!e
me$!+ni$+l propertie o? ?ibrill+r tru$ture 4ere $!+r+$teri<e" b2 APM topo'r+p!i$ "+t+
4!i$! en+ble" t!e +n+l2i o? t!e "e$+2 o? t+n'ent +lon' t!e ?ibril. *u$! "e$+2 +$$ur+tel2
re?le$t t!e me$!+ni$+l propertie o? t!e ?ibril]ome o? 4!i$! +ppe+r to be ?leLible +n"
ome +re @er2 ti??. /en"in' ri'i"itie ?or "i??erent ?ibril @+r2 b2 + mu$! + > or"er o?
m+'nitu"e. )t 4+ !o4n t!+t t!e m+Mor $ontribution to t!e ?ibrilN ri'i"it2 $ome ?rom t!e
'eneri$ !2"ro'en7bon"in' net4or0 o? b+$0bone7b+$0bone inter+$tion, 4!i$! i
mo"ul+te" b2 i"e7$!+in inter+$tion.
87
1!e +bo@e7"e$ribe" ?in"in' onl2 rein?or$e t!e
!2pot!ei t!+t t!e +bilit2 to ?orm +m2loi" ?ibril i + 'eneri$ propert2 be$+ue t!ee
tru$ture +re t+bili<e" b2 m+in7$!+in inter+$tion o? t!e pol2pepti"e b+$0bone. )t +lo
eLpl+in 4!2 o m+n2 unrel+te" protein ?orm u$! ?ibrill+r +''re'+te.
7>
)t i be$omin' $le+r t!+t $urrentl2 +@+il+ble 4i"el2 ue" enemble7b+e" met!o" be+r
limit+tion t!+t pre@ent ?ull $!+r+$teri<+tion +n" un"ert+n"in' o? protein mi?ol"in' +n"
+''re'+tion p!enomen+. *u$! met!o" pro@i"e + 'ener+l pi$ture o? + 2tem in 4!i$! t!e
in?orm+tion i +@er+'e" o@er t!e enemble o? +ll $on?orm+tion preent in t!e 2tem.
Ho4e@er, mi?ol"in' +n" e+rl2 e@ent in protein +''re'+tion +re too Dui$0 +n" in@ol@e
pe$ie t!+t +re too m+ll ?or eLperiment+l probin' b2 mot $urrentl2 +@+il+ble
te$!niDue. 1!e limit+tion o? t!e $urrent met!o" ?or$e $ientit to loo0 ?or +ltern+ti@e
tool to tu"2 me$!+nim o? mi?ol"in' +n" +''re'+tion. Gi@en t!e in!erent n+no$+le
o? t!ee in'le7mole$ule e@ent, it i ine@it+ble t!+t eLitin' +n" emer'in' n+noim+'in'
tool 4ill be +pplie" to ol@e t!ee $!+llen'in' problem b2 openin' ne4 poibilitie to
un"ert+n" t!e me$!+nim o? protein "ie+e, to impro@e "i+'noi +n" to "e@elop
e??e$ti@e t!er+peuti$ +ppro+$!e. (urrent tren" +n" +"@+n$e in n+no$ien$e in"i$+te
t!+t in'le7mole$ule met!o" mi'!t !elp to o@er$ome t!e limit+tion o? $urrentl2 ue"
met!o".
Por eL+mple, re$ent tu"ie uin' in'le7mole$ule ?luore$en$e reon+n$e ener'2 tr+n?er
(*M7P8:1) +n" ?luore$en$e $orrel+tion pe$tro$op2 in@eti'+te" t!e tru$ture +n"
"2n+mi$ o? monomeri$ prion 2e+t protein *up%5.
88
1!e reult o? t!i tu"2
"emontr+te" t!+t t!e 5M p+rt (57termin+l +n" Mi""le p+rt) o? t!e monomeri$ protein
+$$ommo"+te +n enemble o? $on?orm+tion in p!2iolo'i$+l bu??er. 1!e enemble
$onit o? r+pi"l2 inter$on@ertin' $omp+$t $on?orm+tion in"i$+tin' t!e !i'!l2 "2n+mi$
n+ture o? protein $on?orm+tion+l p+$e.
1!i tu"2 rein?or$e" t!e i"e+ t!+t ne4 eLperiment+l tool +re reDuire" to ?ull2
$!+r+$teri<e protein mi?ol"in' +n" +''re'+tion +t t!e le@el o? in'le mole$ule. *u$!
tool 4ill +llo4 un+mbi'uou me+urement o? t!e 0ineti$ o? inter$on@erion bet4een
"i??erent protein $on?orm+tion +n" "itin'ui! $on?orm+tion+l $!+n'e in in"i@i"u+l
protein mole$ule prior to +''re'+tion + 4ell + $!+n'e in"u$e" b2 inter+$tion o?
protein 4it! +not!er protein or ot!er ?+$tor. )t i +lo import+nt to note t!+t ome
$on?orm+tion (mi?ol"e" t+te) mi'!t be more import+nt in +''re'+tion p+t!4+2 t!+n
ot!er e@en t!ou'! t!e2 +re onl2 tr+nientl2 popul+te". 1!e tr+nient n+ture o? mi?ol"e"
$on?orm+tion m+0e t!em not +men+ble to tr+"ition+l met!o". 5e4 tool +re emer'in'
4!i$! +re $+p+ble o? +""rein' t!e mi?ol"in' p!enomenon +t t!e le@el o? + in'le
mole$ule.
1!e tr+nient n+ture o? mi?ol"e" $on?orm+tion +n" el?7prop+'+tin' n+ture o? +m2loi"
!i'!li'!t t!e import+n$e o? un"ert+n"in' 4!+t inter+$tion bet4een protein mole$ule
"ri@e t!e ?orm+tion o? + t+ble nu$leu o? +''re'+tion. Mi?ol"e" +''re'+tion7prone
$on?orm+tion o? + protein mole$ule "i??er ?rom ot!er $on?orm+tion b2 t!eir en!+n$e"
propenit2 to +o$i+te 4it! e+$! ot!er, promotin' ?orm+tion o? n+no7+''re'+te.
89
A
monomeri$ protein !oul" un"er'o tru$tur+l reor'+ni<+tion to +"opt +n interme"i+te
$on?orm+tion+l t+te reDuire" ?or t!e initi+tion o? +''re'+tion.
90
1!e propenit2 ?or u$!
+"+pt+tion $oul" be mo"ul+te" b2 + prim+r2 eDuen$e or eLtern+l ?+$tor u$! +
en@ironment+l $on"ition, inter+$tion 4it! ot!er protein, toLin, $ellul+r $omponent
+n"&or $ellul+r membr+ne.
8e$entl2, +tomi$ ?or$e pe$tro$op2 in'le7mole$ule un?ol"in' met!o"olo'2 !+ been
+pplie" to tu"2 t!e +m2loi"o'eni$ propertie o? m27mi$ro'lobulin
91
+n" t!e
$on?orm+tion+l "i@erit2 o? +lp!+72nu$lein]+ protein in@ol@e" in P+r0inonN "ie+e.
92

A in'le7protein mole$ule 4+ ?l+n0e" b2 t!ree )27 "om+in, 4!i$! +$te" + mole$ul+r
!+n"le + 4ell + + 4ell7i"enti?i+ble ?in'erprint in t!e me+ure" ?or$e $ur@e +llo4in'
$le+r re$o'nition o? i'n+l ?rom me$!+ni$+l tret$!in' o? in'le +lp!+72nu$lein
mole$ule. *u$! +n +ppro+$! probe t!e ?ull $on?orm+tion+l p+$e o? t!e protein,
i"enti?2in' e@en poorl2 popul+te" $on?ormer o? +lp!+72nu$lein. 1!ree m+in "itin$t
$on?orm+tion 4ere i"enti?ie" +n" $l+i?ie" + r+n"om $oil, me$!+ni$+ll2 4e+0 +n"
bet+7li0e tru$ture. 1!e l+tter +re "ire$tl2 rel+te" to +''re'+tion o? +lp!+72nu$lein.
92

)nteretin'l2, p+t!olo'i$+l $on"ition 4!i$! +re 0no4n to in$re+e propenit2 o? +lp!+7
2nu$lein to +''re'+te, u$! + !i'! ioni$ tren't! +n" preen$e o? (u
2[
, !i?te"
$on?orm+tion+l eDuilibrium to4+r" bet+7li0e tru$ture. Alo, t!i +ppro+$! 4+ ue" to
$!+r+$teri<e p+t!olo'i$+l mut+nt o? +lp!+72nu$lein]A%0P, A5%1 +n" :>66.
9%
1!e
tu"2 re@e+le" i'ni?i$+nt "i??eren$e in t!e $on?orm+tion+l be!+@ior o? t!e mut+nt
$omp+re" to t!e 4il"7t2pe protein. All mut+nt !+" !i'!er popul+tion o? bet+7li0e
tru$ture, in"i$+tin' t!eir !i'!er propenit2 to +''re'+te.
9%
1!e +bo@e7"e$ribe" tu"ie rein?or$e" t!e !2pot!ei propoe" e+rlier t!+t mi?ol"e"
$on?orm+tion 4!i$! +re $+p+ble o? tri''erin' protein +''re'+tion +re $!+r+$teri<e" b2
ele@+te" propenit2 to inter+$t 4it! one +not!er.
9>
1!e ue o? APM ?or$e pe$tro$op2 !+
been propoe" to probe t!e propertie o? inter+$tin' in"i@i"u+l mole$ule o? t!e
+''re'+tin' protein.
9>,95
1!e tr+te'2 ?or u$! $!+r+$teri<+tion i "e$ribe" in "et+il
ele4!ere.
89,96,97
/rie?l2, in"i@i"u+l mole$ule +re $o@+lentl2 +tt+$!e" to APM tip +n" t!e
probe" ur?+$e uin' re$entl2 "e@elope" ur?+$e $!emitr2.
89
1!e "imer $+n ?orm 4!en
t!e tip +ppro+$!e t!e ubtr+te +n" t!e inter+$tin' ?or$e bet4een mole$ule 4it!in
"imeri$ $ont+$t +re me+ure" upon tip retr+$tion. M$Alliter et +l.
9>
!+@e ue" APM to
tu"2 mi?ol"in', in"u$in' inter+$tion in t!ree "i??erent +n" tru$tur+ll2 "itin$ti@e
protein: w72nu$lein, +m2loi" m7pepti"e (Am) +n" l2o<2me. 1!e tren't! o? interprotein
inter+$tion 4+ me+ure" +t @+riou pH @+lue, uin' pH + + timul+tin' ?+$tor ?or
$on?orm+tion+l $!+n'e in t!e protein. 3o4 pH @+lue +re 0no4n to in"u$e mi?ol"in'
o? t!ee protein promotin' +''re'+tion +n" imult+neoul2 $on?orm+tion+l tr+nition to
m7t2pe tru$ture.
98
1!e propenit2 o? + protein ?or +''re'+tion, it +$Duiition o? m7!eet
$on?orm+tion +n" tren't! o? interprotein inter+$tion 4ere ?oun" to $orrel+te @er2 4ell,
u''etin' intim+te rel+tion!ip +mon' +ll t!ree.
9>
1!e reult o? t!i tu"2 illutr+te t!e
po4er o? ?or$e pe$tro$op2 in +""rein' mole$ul+r me$!+nim o? protein mi?ol"in'
+n" +''re'+tion b2 me+urin' t!e tren't! o? interprotein inter+$tion.
89,9>
A re$ent
+ppli$+tion o? t!i in'le7mole$ule +ppro+$! to +lp!+ 2nu$lein
97
le" to + ?in"in' t!+t t!e
?orm+tion o? + "imer o? mi?ol"e" +lp!+72nu$lein "r+m+ti$+ll2 in$re+e t!e li?etime o?
t!e protein mi?ol"e" t+te. *u$! t+bili<+tion o? mi?ol"e" protein in + "imeri$ ?orm
enormoul2 in$re+e t!e propenit2 to +''re'+te ?urt!er. 1!i i + ?un"+ment+l ?in"in'
u''etin' t!+t "imeri<+tion o? +m2loi"o'eni$ protein tri''er t!e ?orm+tion o? t!e
"ie+e7prone +emblie +n" t!u initi+tin' t!e "ie+e.
;e !+@e ue" t!i po4er?ul ?or$e pe$tro$op2 +ppro+$! to +n+l2<e inter+$tion bet4een
in"i@i"u+l mole$ule o? t!e !ort pepti"e (G55OO5Y 4it! + $2teine in$orpor+te" to
?+$ilit+te immobili<+tion o? t!e pepti"e ?or t!e ?or$e pe$tro$op2 tu"ie. 1!i pepti"e i
+ p+rt o? *up%5 2e+t prion protein +n" 4+ ?oun" to be +m2loi"o'eni$, ee"in'
+''re'+tion o? t!e entire protein.
99
1!e +''re'+tion o? t!i pepti"e reult in +''re'+te o?
?ibrill+r morp!olo'2 in + 4i"e r+n'e o? en@ironment+l $on"ition. 1!e +''re'+tion
0ineti$ ?or t!i pepti"e 4+ ober@e" to be t!e ?+tet +t pH 5.6 +mon' +ll tete" pH
@+lue.
100
;e !+@e $!oen pH F 5.6 to me+ure t!e inter+$tion bet4een in"i@i"u+l
pepti"e. 1!e pepti"e monomer 4ere $o@+lentl2 +tt+$!e" to APM tip +n" mi$+ ur?+$e
uin' termin+l $2teine rei"ue 4it! ur?+$e $!emitr2 pre@ioul2 "e@elope" +n" tete".
89

Me+urement o? rupture ?or$e o@er + r+n'e o? lo+"in' r+te reulte" in + "2n+mi$ ?or$e
pe$trum (#P*). 3igure ;A !o4 t!e #P* plot obt+ine" ?or inter+$tion bet4een
(G55OO5Y pepti"e +t pH 5.6. 1!e plot !+ @er2 "itin$t p+rt 4!i$! "i@i"e #P* into
e@er+l lope. #io$i+tion o? intermole$ul+r $ont+$t t!+t in@ol@e o@er$omin' more
t!+n one +$ti@+tion b+rrier reult in + "2n+mi$ ?or$e pe$trum 4it! e@er+l
"itin'ui!+ble line+r re'ime $!+r+$teri<e" b2 "i??erent lope.
101
)? t!e "2n+mi$ ?or$e
pe$trum i "i@i"e" into t4o p+rt, +umin' t4o line+r re'ime in t!e r+n'e o? lo+"in'
r+te bet4een 200 +n" 120,000 p5&e$, t!ee t4o lope o? #P* plot ?or t!e pepti"e7
pepti"e "imeri$ $ont+$t +re tr+nl+te" into t4o +$ti@+tion ener'2 b+rrier. A @er2 teep
line+r plot $!+r+$teri<e t!e rupture ?or$e "epen"en$e +t !i'! lo+"in' r+te. 1!i lope
pro"u$e t!e o??7r+te "io$i+tion $ont+nt + !i'! + 1>7
H1
4!en ?itte" 4it! /ellN
mo"el.
101
1!e e$on" re'ime +t lo4 lo+"in' r+te i $!+r+$teri<e" b2 + mu$! m+ller
@+lue o? o??7r+te $ont+nt, 0o?? F 1.8
H1
. 1!e "imer li?etime $orrepon"in' to t!i @+lue o?
o?? r+te $ont+nt 4+ ?oun" to be 0.6 e$on", u''etin' !i'! t+bilit2 o? "imeri$ pe$ie
$omp+re" to t!e "2n+mi$ $!+r+$teriti$ o? t!e protein in monomeri$ t+te.
100
1!e "imer,
t!u, m+2 er@e + t+ble nu$lei ?or t!e ?orm+tion o? multimeri$ +n" +''re'+te" ?orm o?
t!e pepti"e. 1!i ober@+tion i in line 4it! + pre@iou tu"2 t!+t u''ete" + $riti$+l role
o? "imeri<+tion in t!e +''re'+tion o? +72nu$lein.
97
Moreo@er, + imil+r p+ttern 4+
ober@e" ?or Am7>0 pepti"e.
100
1!u, +ll "+t+ le+" to + ne4 mo"el o? t!e protein
+''re'+tion in 4!i$! t!e @er2 ?irt t+'e, t!e ?orm+tion o? "imer, i + 0e2 tep tri''erin'
t!e entire el?7+embl2 pro$e.
Pi'ure %
#2n+mi$ ?or$e pe$trum o? (G55OO5Y pepti"e inter+$tion me+ure" +t pH 5.6.
)n $on$luion, 4e belie@e t!+t ?urt!er eLploit+tion o? in'le7mole$ule +ppro+$!e 4ill
pro@i"e ne4 import+nt ini'!t into t!e me$!+nim o? protein mi?ol"in' +n"
+''re'+tion. ;e +nti$ip+te t!+t in'le7mole$ule met!o" 4ill +"@+n$e our un"ert+n"in'
o? u$! p!enomen+ + mi?ol"in', +''re'+tion +n" n+ture o? toLi$ pe$ie. *u$!
0no4le"'e i $riti$+l ?or $ontrollin' t!ee pro$ee +n" t!e "e@elopment o? e??e$ti@e
t!er+peuti$ +'ent to pre@ent rel+te" neuro"e'ener+ti@e "ie+e.
Go to:
Acknowledgements
1!e +ut!or t!+n0 3u"+ *. *!l2+0!ten0o ?or !er !elp 4it! APM im+'in'.
Go to:
3ootnotes
Pre@ioul2 publi!e" online: 444.l+n"ebio$ien$e.$om&Mourn+l&prion&+rti$le&1%125
Go to:
3inancial &upport
1!e 4or0 4+ upporte" b2 t!e ?ollo4in' 'r+nt: #E: (#:7PG02708:86>579) +n"
5A1E ((/5.58.58*PP 98%20>) (+ll to Y.3.3.).
Go to:
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7. /+lb+$! --, Pet0o@+ A1, E2ler 5A, Ant<ut0in E5, Gor"on #-, Mere"it! *(, et +l.
*upr+mole$ul+r tru$ture in ?ull7len't! Al<!eimerN bet+7+m2loi" ?ibril: e@i"en$e ?or +
p+r+llel bet+7!eet or'+ni<+tion ?rom oli"7t+te nu$le+r m+'neti$ reon+n$e. /iop!2 -.
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5M8 re@e+l + pH7"epen"ent +ntip+r+llel bet+7!eet re'itr2 in ?ibril ?orme" b2 + bet+7
+m2loi" pepti"e. - Mol /iol. 200>;%%5:2>7260. IPubMe"J
9. *+4+2+ M8, *+mb+!i@+n *, 5elon 8, )@+no@+ M), *ie@er *A, Apotol M), et +l.
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11. 1eni"i 6, ;+l"ner M, /ern!+'en -, Pi$!le ;, /er'm+nn M, ;eber M, et +l.
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1%. )@+no@+ M), *+4+2+ M8, Gin'er2 M, Attin'er A, :ienber' #. An +m2loi"7?ormin'
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*$i .*A. 200>;101:1058>10589. IPM( ?ree +rti$leJ IPubMe"J
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2%. /+n 1, H+m+"+ #, H+e'+4+ 6, 5+i0i H, Goto Y. #ire$t ober@+tion o? +m2loi"
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26. Ho2er ;, (!ern2 #, *ubr+m+ni+m =, -o@in 1M. 8+pi" el?7+embl2 o? +lp!+7
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27. 6o4+le40i 1, Holt<m+n #M. )n itu +tomi$ ?or$e mi$ro$op2 tu"2 o? Al<!eimerN
bet+7+m2loi" pepti"e on "i??erent ubtr+te: ne4 ini'!t into me$!+nim o? bet+7!eet
?orm+tion. Pro$ 5+tl A$+" *$i .*A. 1999;96:%688%69%. IPM( ?ree +rti$leJ IPubMe"J
28. Gol"bur2 (, 6itler -, Aebi ., Ar@inte 1, (ooper G-. ;+t$!in' +m2loi" ?ibril 'ro4
b2 time7l+pe +tomi$ ?or$e mi$ro$op2. - Mol /iol. 1999;285:%%%9. IPubMe"J
29. Gol"bur2 (, Green -. 1ime7l+pe +tomi$ ?or$e mi$ro$op2 in t!e $!+r+$teri<+tion o?
+m2loi"7li0e ?ibril +embl2 +n" oli'omeri$ interme"i+te. Met!o" Mol /iol.
2005;299:10%128. IPubMe"J
%0. 6ellerm+2er M*, 6+r+i A, /en0e M, *oo 6, Pen0e /. *tep4ie "2n+mi$ o?
epit+Li+ll2 'ro4in' in'le +m2loi" ?ibril. Pro$ 5+tl A$+" *$i .*A. 2008;105:1>11>>.
%1. #eP+$e AH, ;eim+n -*. Eri'in +n" 0ineti$ $oneDuen$e o? "i@erit2 in *up%5
2e+t prion ?iber. 5+t *tru$t /iol. 2002;9:%89%96. IPubMe"J
%2. Pruiner */. Prion. Pro$ 5+tl A$+" *$i .*A. 1998;95:1%%6%1%%8%. IPM( ?ree
+rti$leJ IPubMe"J
%%. Mor+le 8, Abi" 6, *oto (. 1!e prion tr+in p!enomenon: mole$ul+r b+i +n"
unpre$e"ente" ?e+ture. /io$!im /iop!2 A$t+. 2007;1772:681691. IPM( ?ree +rti$leJ
IPubMe"J
%>. Pet0o@+ A1, 3e+pm+n 8#, Guo A, Y+u ;M, M+tton MP, 12$0o 8. *el?7prop+'+tin',
mole$ul+r7le@el pol2morp!im in Al<!eimerN bet+7+m2loi" ?ibril. *$ien$e.
2005;%07:262265. IPubMe"J
%5. 1+n+0+ M, (!ien P, Yone0ur+ 6, ;eim+n -*. Me$!+nim o? $ro7pe$ie prion
tr+nmiion: +n in?e$tiou $on?orm+tion $omp+tible 4it! t4o !i'!l2 "i@er'ent 2e+t
prion protein. (ell. 2005;121:>962. IPubMe"J
%6. -one :M, *ure4i$< ;6. Pibril $on?orm+tion + t!e b+i o? pe$ie7 +n" tr+in7
"epen"ent ee"in' pe$i?i$it2 o? m+mm+li+n prion +m2loi". (ell. 2005;121:6%72.
IPubMe"J
%7. M+0+r+@+ 5, Et+p$!en0o =G, *+@t$!en0o 8, /+0+0o@ )=. (on?orm+tion+l
4it$!in' 4it!in in"i@i"u+l +m2loi" ?ibril. - /iol (!em. 2009;28>:1>%861>%95. IPM(
%8. @+n "er ;el P(, 3e4+n"o40i -8, Gri??in 8G. *oli"7t+te 5M8 tu"2 o? +m2loi"
n+no$r2t+l +n" ?ibril ?orme" b2 t!e pepti"e G55OO5Y ?rom 2e+t prion protein
*up%5p. - Am (!em *o$. 2007;129:511751%0. IPubMe"J
%9. 5o@it0+2+ =, M+0+r+@+ 5, /ellon A, /o$!+ro@+ E=, /rontein )/, ;illi+mon 8A,
et +l. Probin' t!e $on?orm+tion o? t!e prion protein 4it!in + in'le +m2loi" ?ibril uin' +
no@el immuno$on?orm+tion+l ++2. - /iol (!em. 2006;281:155%6155>5. IPubMe"J
>0. Pett2 *A, #e$+tur *M. )nter!eet re+rr+n'ement o? pol2pepti"e "urin' nu$le+tion o?
kbet+l7!eet +''re'+te. Pro$ 5+tl A$+" *$i .*A. 2005;102:1>2721>277. IPM( ?ree
+rti$leJ IPubMe"J
>1. *!im *H, Gupt+ 8, 3in' Y3, *tr+?el" #/, 8+lei'! #P, A+nni M1. 14o7"imenion+l
)8 pe$tro$op2 +n" iotope l+belin' "e?ine t!e p+t!4+2 o? +m2loi" ?orm+tion 4it!
rei"ue7pe$i?i$ reolution. P 5+tl A$+" *$i .*A. 2009;106:661>6619. IPM( ?ree
+rti$leJ IPubMe"J
>2. *!+!ilo@ =, û M, :rmolen0o@ ==, Pre"ri0en 3, 3e"ne@ )6. Probin' + ?ibrill+tion
nu$leu "ire$tl2 b2 "eep ultr+@iolet 8+m+n pe$tro$op2. - Am (!em *o$.
2007;129:6972697%. IPubMe"J
>%. *!+!ilo@ =A, 3e"ne@ )6. 2# $orrel+tion "eep .= reon+n$e r+m+n pe$tro$op2 o?
e+rl2 e@ent o? l2o<2me ?ibrill+tion: 0ineti$ me$!+nim +n" potenti+l interpret+tion
pit?+ll. - Am (!em *o$. 2008;1%0:%09%17. IPubMe"J
>>. P+ulite M, P+0!r++i A, Gun+ri 5, 1+nur A, G; #i??erent )n"i@i"u+l Am2loi" Pibril
:L!ibit #i??erent /et+ *!eet *e$on"+r2 *tru$ture @i+ 5e+r7?iel" )n?r+re" *pe$tro$op2.
/iop!2 -. 2009;96:87.
>5. P+ulite M, P+0!r++i A, A0!remit$!e@ //, Mueller 6, ;+l0er G(. Aembl2, tunin'
+n" ue o? +n +perturele ne+r ?iel" in?r+re" mi$ro$ope ?or protein im+'in'. - =i :Lp.
2009 IPM( ?ree +rti$leJ IPubMe"J
>6. *to$0le 8M, *u! Y#, #e$0ert =, Aenobi 8. 5+no$+le $!emi$+l +n+l2i b2 tip7
en!+n$e" 8+m+n pe$tro$op2. (!em P!2 3ett. 2000;%18:1%11%6.
>7. H+2+<+4+ 5, )nou2e Y, *e00+t A, 6+4+t+ *. Met+lli<e" tip +mpli?i$+tion o? ne+r7
?iel" 8+m+n $+tterin'. Epti$ (ommuni$+tion. 2000;18%:%%%%%6.
>8. Pettin'er /, Pi$+r"i G, *$!uter G, :rtl G. *ur?+$e en!+n$e" 8+m+n pe$tro$op2:
to4+r" in'le mole$ule pe$tro$op2. :le$tro$!em. 2000;68:9>29>9.
>9. /+ilo :, #e$0ert =. 1ip7en!+n$e" 8+m+n $+tterin'. (!em *o$ 8e@. 2008;%7:921
9%0. IPubMe"J
50. 5e+$u ((, #re2er -, /e!r 5, 8+$!0e M/. 8epl2 to (omment on o*$+nnin'7probe
8+m+n pe$tro$op2 4it! in'le7mole$ule eniti@it2p P!2 8e@ /. 2007;75:2%6>02.
51. /+ilo :, #e$0ert =. 1ip7en!+n$e" 8+m+n pe$tro$op2 o? in'le 85A tr+n":
to4+r" + no@el "ire$t7eDuen$in' met!o". An'e4 (!em )nt :" :n'l. 2008;>7:1658
1661. IPubMe"J
52. #e$0ert7G+u"i' 1, #e$0ert =. .ltr+?l+t tr+np+rent 'ol" n+nopl+te]i"e+l ubtr+te
?or tip7en!+n$e" 8+m+n $+tterin' eLperiment. *m+ll. 2009;5:>%2>%6. IPubMe"J
5%. #e$0ert7G+u"i' 1, 8+ul :, #e$0ert =. Arom+ti$ +mino +$i" monol+2er +n"4i$!e"
bet4een 'ol" +n" il@er: + $ombine" tip7en!+n$e" r+m+n +n" t!eoreti$+l +ppro+$!. -
P!2 (!em (. 2010;11>:7>127>20.
5>. *!orter -, 3in"Duit *. Prion + +"+pti@e $on"uit o? memor2 +n" in!erit+n$e. 5+t
8e@ Genet. 2005;6:>%5>50. IPubMe"J
55. H+rri #A, 1rue H3. 5e4 ini'!t into prion tru$ture +n" toLi$it2. 5euron.
2006;50:%5%%57. IPubMe"J
56. Alberti *, H+l?m+nn 8, 6in' E, 6+pil+ A, 3in"Duit *. A 2tem+ti$ ur@e2 i"enti?ie
prion +n" illumin+te eDuen$e ?e+ture o? priono'eni$ protein. (ell. 2009;1%7:1>6
57. 1+n+0+ M, (ollin *8, 1o2+m+ /H, ;eim+n -*. 1!e p!2i$+l b+i o? !o4 prion
$on?orm+tion "etermine tr+in p!enot2pe. 5+ture. 2006;>>2:585589. IPubMe"J
58. 1rue H3. 1!e b+ttle o? t!e ?ol": $!+perone t+0e on prion. 1ren" Genet.
2006;22:110117. IPubMe"J
59. 3e'n+me G, 5'u2en HE, /+0+0o@ )=, (o!en P:, #e+rmon" *-, Pruiner */.
*tr+in7pe$i?ie" $!+r+$teriti$ o? moue 2nt!eti$ prion. Pro$ 5+tl A$+" *$i .*A.
2005;102:2168217%. IPM( ?ree +rti$leJ IPubMe"J
60. 3e'n+me G, 5'u2en HE, Peret< #, (o!en P:, #eArmon" *-, Pruiner */.
(ontinuum o? prion protein tru$ture en$ip!er + multitu"e o? prion iol+te7pe$i?ie"
p!enot2pe. Pro$ 5+tl A$+" *$i .*A. 2006;10%:1910519110. IPM( ?ree +rti$leJ
IPubMe"J
61. *un Y, M+0+r+@+ 5, 3ee (), 3+0+n+l+m+i P, 8obb P1, /+0+0o@ )=. (on?orm+tion+l
t+bilit2 o? PrP +m2loi" ?ibril $ontrol t!eir m+llet poible ?r+'ment i<e. - Mol /iol.
2008;%76:11551167. IPM( ?ree +rti$leJ IPubMe"J
62. *il@eir+ -8, 8+2mon" G-, Hu'!on AG, 8+$e 8:, *im =3, H+2e *P, et +l. 1!e mot
in?e$tiou prion protein p+rti$le. 5+ture. 2005;>%7:257261. IPM( ?ree +rti$leJ
IPubMe"J
6%. 3+mbert MP, /+rlo4 A6, (!rom2 /A, :"4+r" (, Pree" 8, 3io+to M, et +l.
#i??uible, non?ibrill+r li'+n" "eri@e" ?rom Abet+1>2 +re potent $entr+l ner@ou 2tem
neurotoLin. Pro$ 5+tl A$+" *$i .*A. 1998;95:6>>86>5%. IPM( ?ree +rti$leJ IPubMe"J
6>. (on4+2 6A, 3ee *-, 8o$!et -(, #in' 11, H+rper -#, ;illi+mon 8:, et +l.
A$$eler+te" oli'omeri<+tion b2 P+r0inonN "ie+e lin0e" +lp!+72nu$lein mut+nt. Ann
5Y A$+" *$i. 2000;920:>2>5. IPubMe"J
65. *$!er<in'er :, 3ur< 8, 1urm+ine M, M+n'i+rini 3, Hollenb+$! /, H+enb+n0 8, et
+l. Huntin'tin7en$o"e" pol2'lut+mine eLp+nion ?orm +m2loi"7li0e protein +''re'+te
in @itro +n" in @i@o. (ell. 1997;90:5>9558. IPubMe"J
66. 6lein ;3, 6r+??t GA, Pin$! (:. 1+r'etin' m+ll Abet+ oli'omer: t!e olution to +n
Al<!eimerN "ie+e $onun"rum\ 1ren" 5euro$i. 2001;2>:21922>. IPubMe"J
67. H++ (, *el0oe #-. *oluble protein oli'omer in neuro"e'ener+tion: leon ?rom
t!e Al<!eimerN +m2loi" bet+7pepti"e. 5+t 8e@ Mol (ell /iol. 2007;8:101112.
IPubMe"J
68. Gol"ber' M*, 3+nbur2 P1., -r ) t!ere + $+ue7+n"7e??e$t rel+tion!ip bet4een
+lp!+72nu$lein ?ibrilli<+tion +n" P+r0inonN "ie+e\ 5+t (ell /iol. 2000;2:115119.
IPubMe"J
69. Erte A, /ir0ett 58, (l+r0e 8;, #e@lin G3, #obon (M, 6lenerm+n #. #ire$t
$!+r+$teri<+tion o? +m2loi"o'eni$ oli'omer b2 in'le7mole$ule ?luore$en$e. P 5+tl
A$+" *$i .*A. 2008;105:1>>2>1>>29. IPM( ?ree +rti$leJ IPubMe"J
70. *erio 18, (+!i0+r AG, 6o4+l A*, *+4i$0i G-, Mole!i --, *erpell 3, et +l.
5u$le+te" $on?orm+tion+l $on@erion +n" t!e repli$+tion o? $on?orm+tion+l in?orm+tion
b2 + prion "etermin+nt. *$ien$e. 2000;289:1%171%21. IPubMe"J
71. He ^, Giurleo -1, 1+l+'+ #*. 8ole o? m+ll oli'omer on t!e +m2loi"o'eni$
+''re'+tion ?ree7ener'2 l+n"$+pe. - Mol /iol. 2009;%95:1%>15>. IPM( ?ree +rti$leJ
IPubMe"J
72. Moore 8A, =orber' ), Priol+ *A. *pe$ie b+rrier in prion "ie+e]brie? re@ie4.
Ar$! =irol. 2005:187202. IPubMe"J
7%. =+ni0 #3, *ure4i$< 6A, *ure4i$< ;6. Mole$ul+r b+i o? b+rrier ?or interpe$ie
tr+nmiibilit2 o? m+mm+li+n prion. Mol (ell. 200>;1>:1%91>5. IPubMe"J
7>. (!iti P, #obon (M. Protein mi?ol"in', ?un$tion+l +m2loi" +n" !um+n "ie+e.
Annu 8e@ /io$!em. 2006;75:%%%%66. IPubMe"J
75. (!en /, /ru$e 63, 5e4n+m GP, G2one@+ *, 8om+n2u0 A=, (!erno?? YE. Geneti$
+n" epi'eneti$ $ontrol o? t!e e??i$ien$2 +n" ?i"elit2 o? $ro7pe$ie prion tr+nmiion.
Mol Mi$robiol. 2010;76:1>8%1>99. IPM( ?ree +rti$leJ IPubMe"J
76. (!en /, 5e4n+m GP, (!erno?? YE. Prion pe$ie b+rrier bet4een t!e $loel2 rel+te"
2e+t protein i "ete$te" "epite $o+''re'+tion. Pro$ 5+tl A$+" *$i .*A.
2007;10>:27912796. IPM( ?ree +rti$leJ IPubMe"J
77. #obon (M. Prin$iple o? protein ?ol"in', mi?ol"in' +n" +''re'+tion. *emin (ell
#e@ /iol. 200>;15:%16. IPubMe"J
78. #obon (M. Protein mi?ol"in', e@olution +n" "ie+e. 1ren" /io$!em *$i.
1999;2>:%29%%2. IPubMe"J
79. Pet0o@+ A1, )!ii Y, /+lb+$! --, Ant<ut0in E5, 3e+pm+n 8#, #el+'lio P, et +l. A
tru$tur+l mo"el ?or Al<!eimerN bet+7+m2loi" ?ibril b+e" on eLperiment+l $ontr+int
?rom oli" t+te 5M8. Pro$ 5+tl A$+" *$i .*A. 2002;99:167>2167>7. IPM( ?ree
+rti$leJ IPubMe"J
80. Perut< MP, -o!non 1, *u<u0i M, Pin$! -1. Glut+mine repe+t + pol+r <ipper: t!eir
poible role in in!erite" neuro"e'ener+ti@e "ie+e. Pro$ 5+tl A$+" *$i .*A.
199>;91:5%555%58. IPM( ?ree +rti$leJ IPubMe"J
81. ;+ton #, (+t+no :, 6o0Mo!n 1A, 6uo YM, 32ub$!en0o Y, Pin02 #, et +l.
P!2i$o$!emi$+l $!+r+$teriti$ o? oluble oli'omeri$ Abet+ +n" t!eir p+t!olo'i$ role in
Al<!eimerN "ie+e. 5eurol 8e. 2005;27:869881. IPubMe"J
82. (!en *, Perrone PA, ;et<el 8. Huntin'tonN "ie+e +'e7o?7onet lin0e" to
pol2'lut+mine +''re'+tion nu$le+tion. Pro$ 5+tl A$+" *$i .*A. 2002;99:1188>11889.
8%. GuiM+rro -), *un"e M, -one -A, (+mpbell )#, #obon (M. Am2loi" ?ibril ?orm+tion
b2 +n *H% "om+in. Pro$ 5+tl A$+" *$i .*A. 1998;95:>22>>228. IPM( ?ree +rti$leJ
IPubMe"J
8>. (!iti P, ;ebter P, 1+""ei 5, (l+r0 A, *te?+ni M, 8+mponi G, et +l. #ei'nin'
$on"ition ?or in @itro ?orm+tion o? +m2loi" proto?il+ment +n" ?ibril. Pro$ 5+tl A$+"
*$i .*A. 1999;96:%590%59>. IPM( ?ree +rti$leJ IPubMe"J
85. /+"er 8, /+m?or" 8, Aur"o -, 3uii /P, #obon (M. Probin' t!e me$!+nim o?
+m2loi"o'enei t!rou'! + t+n"em repe+t o? t!e P)%7*H% "om+in u''et + 'eneri$
mo"el ?or protein +''re'+tion +n" ?ibril ?orm+tion. - Mol /iol. 2006;%56:189208.
IPubMe"J
86. Pell+rin 8, (+?li$! A. )nterpretin' t!e +''re'+tion 0ineti$ o? +m2loi" pepti"e. -
Mol /iol. 2006;%60:882892. IPubMe"J
87. 6no4le 1P, Pit<p+tri$0 A;, Mee!+n *, Mott H8, =en"ru$olo M, #obon (M, et +l.
8ole o? intermole$ul+r ?or$e in "e?inin' m+teri+l propertie o? protein n+no?ibril.
*$ien$e. 2007;%18:1900190%. IPubMe"J
88. Mu0!op+"!2+2 *, 6ri!n+n 8, 3em0e :A, 3in"Duit *, #eni< AA. A n+ti@el2
un?ol"e" 2e+t prion monomer +"opt +n enemble o? $oll+pe" +n" r+pi"l2 ?lu$tu+tin'
tru$ture. Pro$ 5+tl A$+" *$i .*A. 2007;10>:26>9265>. IPM( ?ree +rti$leJ IPubMe"J
89. 6r+nnolobo"te@ A=, *!l2+0!ten0o 3*, .0r+inte@ :, A+i0o@+ 1E, 6e+n+ -P,
32ub$!en0o Y3. 5+nome"i$ine +n" protein mi?ol"in' "ie+e. 5+nome"i$ine.
2005;1:%00%05. IPM( ?ree +rti$leJ IPubMe"J
90. 8ubintein A, 32ub$!en0o Y3, *!erm+n *. #2n+mi$ propertie o? pH7"epen"ent
tru$tur+l or'+ni<+tion o? t!e +m2loi"o'eni$ bet+7protein (1>0) Prion. 2009;%:%1>%.
91. *or$e /, *+bell+ *, *+n"+l M, *+mori /, *+ntino A, (in'ol+ni 8, et +l. *in'le7
mole$ule me$!+ni$+l un?ol"in' o? +m2loi"o'eni$ bet+(2)7mi$ro'lobulin: 1!e ?or$e7
pe$tro$op2 +ppro+$!. (!emp!2$!em. 2009;10:1>711>77. IPubMe"J
92. *+n"+l M, =+lle P, 1e+ri ), M+mmi *, /er'+ntino :, Mui+ni P, et +l.
(on?orm+tion+l eDuilibri+ in monomeri$ +lp!+72nu$lein +t t!e in'le7mole$ule le@el.
P3o* /iol. 2008;6:6. IPM( ?ree +rti$leJ IPubMe"J
9%. /ru$+le M, *+n"+l M, #i M+io *, 8+mpioni A, 1e+ri ), 1o+tto 3, et +l. P+t!o'eni$
mut+tion !i?t t!e eDuilibri+ o? +lp!+72nu$lein in'le mole$ule to4+r" tru$ture"
$on?ormer. (!embio$!em. 2009;10:17618%. IPubMe"J
9>. M$Alliter (, 6+r2mo@ MA, 6+4+no Y, 3u!ni0o@ AY, Mi0!ei0in A, .@er02 =5,
et +l. Protein inter+$tion +n" mi?ol"in' +n+l2<e" b2 APM ?or$e pe$tro$op2. - Mol
/iol. 2005;%5>:102810>2. IPubMe"J
95. 32ub$!en0o Y3, *!erm+n *, *!l2+0!ten0o 3*, .@er02 =5. 5+noim+'in' ?or
protein mi?ol"in' +n" rel+te" "ie+e. - (ell /io$!em. 2006;99:5%70. IPM( ?ree
+rti$leJ IPubMe"J
96. Yu -, 32ub$!en0o Y3. :+rl2 t+'e ?or P+r0inonN "e@elopment: +lp!+72nu$lein
mi?ol"in' +n" +''re'+tion. - 5euroimmune P!+rm. 2009;>:1016. IPubMe"J
97. Yu -, M+l0o@+ *, 32ub$!en0o Y3. +lp!+7*2nu$lein mi?ol"in': in'le mole$ule APM
?or$e pe$tro$op2 tu"2. - Mol /iol. 2008;%8>:9921001. IPubMe"J
98. Perut< MP, Pope /-, E4en #, ;+n0er ::, *$!er<in'er :. A''re'+tion o? protein
4it! eLp+n"e" 'lut+mine +n" +l+nine repe+t o? t!e 'lut+mine7ri$! +n" +p+r+'ine7ri$!
"om+in o? *up%5 +n" o? t!e +m2loi" bet+7pepti"e o? +m2loi" pl+Due. Pro$ 5+tl A$+"
*$i .*A. 2002;99:55965600. IPM( ?ree +rti$leJ IPubMe"J
99. /+lbirnie M, Grot!e 8, :ienber' #*. An +m2loi"7?ormin' pepti"e ?rom t!e 2e+t
prion *up%5 re@e+l + "e!2"r+te" bet+7!eet tru$ture ?or +m2loi". Pro$ 5+tl A$+" *$i
.*A. 2001;98:2%752%80. IPM( ?ree +rti$leJ IPubMe"J
100. 32ub$!en0o Y, 6im /H, 6r+nolobo"te@ A, Yu -. 5+noim+'in' ?or protein
mi?ol"in' "ie+e. ;ile2 )nter"i$iplin+r2 8e@ie4: 5+nome"i$ine +n"
5+nobiote$!nolo'2. 2010 IPubMe"J
101. Mer0el 8, 5+o2 P, 3eun' A, 8it$!ie 6, :@+n :. :ner'2 l+n"$+pe o? re$eptor7
li'+n" bon" eLplore" 4it! "2n+mi$ ?or$e pe$tro$op2. 5+ture. 999;%97:505%.
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