neirodegeneraciuli

daavadebebi

daunis sindromi
I
 daunis sindromis dros
kognitiur unaris
gaumjobesebaze mimarTuli
farmakoTerapiis
molekuluri safuZvlebi
 daunis sindromis Seswavlis istoria

John Langdon Down (britaneli eqimi)-1866

wels pirvelad aRwera es sindromi

Jerome Lejeune (frangi genetikosi)-1958

wels pirvelma daadgina rom daavadeba
21-e qromosomis trisomiiTaa
ganpirobebuli
 daunis sindromiT daavadebulTa niSnebi:

• fizikuri zrdis Seferxeba.

• susti kunTebi
• saxis specifikuri
damaxasiaTebeli uCveulod
mrgvali forma
• mikrogenia- zomaze mcire
zomis nikapi
• mcire zomis piris Rru
• makroglosia- zomaze didi ena
• Tvalebis nuSiseburi forma
• patara zomis yurebi
 daunis sindromiT daavadebulTa niSnebi:

• xelis gulze 2 ZiriTadi

nakecis nacvlad 1 nakecis
arseboba da mokle 5-e TiTis
arseboba
• fexis TiTebidan pirveli TiTi
didi daSorebiTaa
ganlagebuli danarCeni
TiTebisadmi
 daunis sindromiT daavadebulTa niSnebi:

• dauniT daavadebuli bavSvebs SeuZliaT

Seasrulon yvela is moqmedeba rasac asruleben
maTi Tanatoli bavSvebi: siaruli, laparaki,
Cacma...
• ubralod isini viTardebian ufro gvian vidre
sxva bavSvebi
• maTi SeTvisebis unari normaze dabalia
• aseve maT aqvT mentaluri problemebi, romlis
farglebi cvalebadobs rameTu mravali maTgani
swavlobs kiTxvasa da weras
 ra iwvevs daunis sindroms?
• Cveulebriv, kvercxujredi da spermatozoidi Seicavs
23 qromosomas
• maTi gaerTianebis Sedegad gametebis Serwymis xarjze
kvercxujredSi viRebT qromosomebis saerTo
raodenobas 23 wyvils anu 46 cals.
 ra iwvevs daunis sindroms?
• rig SemTxvevebSi, sasqeso ujredebi ar viTardeba ise
rogorc saWiroa da maTSi xvdeba 24 qromosoma 23-is
nacvlad
• daunis sindromi viTardeba im SemTxvevaSi Tu es
eqstra qromosoma 21 qromosomaa

• daavadebuli organizmis ujredebSi 3 cali 21-e

qromosomis arsebobis gamo daunis sindromi cnobilia
21 qromosomis trisomiis saxelwodebiTac
 daunis sindromiT daavadebulebSi 21
qromosomis grZeli mxris (HSA21q) eqstra
aslis arseboba
sxvadasxva gziT SeiZleba Camoyalibdes:

• 1. qromosomaTa ganuridebloba
• 2. translokacia
• 3. mozaicizmi
1. qromosomaTa ganuridebloba. (SemTxvevaTa 96 %)

homologiur qromosomaTa
ganuridebloba I meiozis
dros

Svileuli qromatidebis
ganuridebloba II
meiozis dros
2. translokacia (SemTxvevaTa 3 %)
arahomologiur qromosomebs Soris ubnebis gacla,

ds-s dros adgili aqvs

robertsonis translokacias.

esaa translokaciis ti pi,

rodesac ori akrocentruli
qromosoma Seerwymeba erTmaneTs
centromerebTan axlos mokle
mxris dakargvis xarjze.

kerZod ds-s dros 1 asli 21-e

qromosomisa translocirdeba
sxva akrocentrul qromosomaze,
ZiriTadad esaa 14-e qromosoma
akrocentruli qromosomebia:
me-13-e, me-14-e, me-15-e, 21-e, 22-e
 3. mozaicizmi (SemTxvevaTa 1-2%)

pacientebSi SeiniSneba normaluri da

trisomuli ujredebis erTdrouli
arseboba.

aseT pacientebs simptomebis ufro

susti fenotipuri gamovlineba aqvT
daunizmiT daavadebulis kariotipuli ruka

daunizmisas
inteleqtualuri
uunaroba adamainis 21
qromosomis grZeli
mxris (HSA21q) eqstra
aslis arsebobiTaa
ganpirobebuli
 vis aaqvs maRali riski dauniT
daavadebuli bavSvis yolisa

• mSoblebs romelTac ukve yavT dauniT daavadebuli

1 Svili mainc

• dedas romlis asaki 37 welze metia

araferi araa cnoblili ratom xdeba problemebi 21

qromosomasTan dakavSirebiT
 SesaZlebelia Tu ara misi diagnozireba
moxdes fexmZimobis ganmavlobaSi
• sisxlSi alfa fetoproteinis (AFP)
testirebiT, romlis raodenoba dauniT
daavadebulebSi klebulobs
esaa skrining testi, romelic wina pirobaa
Semdegi testebisaTvis:
• amniocentezi- amniozuri siTxis
testireba (AFT ) (keTdeba fexmZimobis 14-16
kviras)
• placentis qsovilis analizi (CVS -
chorionic villus sampling ) -keTdeba
fexmZimobis 10-12 kviras.
 janmrTelobis problemebi dakavSirebuli
daunis sindromTan:
• pacientTa 30-50%-Si SeiniSneba gulis daavadebebi
• nawlavis daavadebebi, romelic operaciul Carevas
saWiroebs. SeimCneva daavadebulTa 10-12%-Si
• mxedvelobiTi da smeniTi gauareseba vlindeba
pacientTa 50%-ze metSi.
• Tiroiduli daavadebebi (hipoTireodizmi emarTebad
ufro xSirad vidre hiperTireodizmi), leikemia,
diabeti, epilepsia, alchaimeris daavadeba maTSi ufro
maRali sixSirisaa
• maRalia infeqciebis riski, imunuri sistemis
Sesustebuli funqcionirebisa da T ujredebis mcire
raodenobis arsebobis gamo.
• piris Rrus simSrale (qserostomia), romelic piriT
sunTqviT aris gamowveuli, TavisTavad iwvevs tuCebisa
da enis daskdomas da zeda sasunTqi gzebis
respiratorul infeqciebs
 gamravlebisunarianoba

• qalebi, romlebic daavdebulebi arian daunis

simptomiT ZiriTadad arian nayofierni da aqvT
SesaZlebloba rom dafexmZimdnen

• TiTqmis yvela mamakaci daunis daavadebiT, aris

unayofo, rac spermatogenezis procesis
darRvevebTanaa dakavSirebuli

• maTi saSualo siscocxlis xangrZlovoba 45-55

welia

• TiTqmis yvela daunis sindromiT daavadebul

adamians uviTardeba alchaimeris daavadeba Tu maT
miaRwies sicocxlis meoTxe dekadas
 tvinis romel ubnebze modis cvlilebebi dauniT
daavadebul adamianebSi

• Tavdapirvelad axaldabadebulebSi tvinis morfologia

normaluria
• postnataluri ganviTareba Seferxebulia hipokampis, naTxemisa
da prefrontaluri korteqsis Semcirebuli moculobis xarjze
• hipokampis ganviTarebis Seferxeba TavisTavad iwvevs daswavlis
procesebSi Seferxebas
• laparakis unarSi darRvevebi
ki prefrontaluri da
temporaluri korteqsisa
da aseve naTxemis ubanTan
aris dakavSirebuli
 metyvelebis problemebi
metyvelebiesTan dakavSirebuli problemebs
ganapirobebs:
• gonebrivi CamorCeniloba
• SedarebiT didi ena mcire zomis piris RruSi
• Warbi nerwyvianoba
• kbilebTan dakavSirebuli problemebi
• smenis problemebi
• afazia- gauareseba metyvelebis daswavlasTan
dakaviSrebiT (sirTuleebi aqvT sityvebis
damaxsovrebasTan dakavSirebiT)
 K ra aris saWiro kognitiuri deficitis
dasaZlevad?

• saWiroa HSA21 qromosomaze ganlagebuli rigi genebis

identificireba, romelic pasuxismebelia kognitiur
deficitze

• yvelaze efeqturi samizneebis identificireba, romelic

CarTulia kognitiur deficitis procesSi

• am samizneebis testireba
 ra qmnis problemas?

• 2000 wels dasrulda HSA21q–is genomis sruli seqvensireba,

Tumca qromosomis am ubanze Seswavlili 500 genidan mxolod
mcire nawilia cilis masinTezirebeli geni, romelic genTa
bankis monacemTa bazaSia

• dadginda rom daunis sindromisTvis

kritikuli ubnis (dsku) trisomia
yovelTvis araa mizezi daunizmis
dros kognitiuri deficitisa

• am genebidanac mxolod daaxloebiT

30% genebis Tanxvedra xdeba
evoluciis sxva safexurze mdgom
cxvelebTan (Simpanze, Tagvi)
 daunis sindromis modeli virTagvebSiA
sirTuleebi virTagvebis
modelebis gamoyvanasTan
dakavSirebiT:

• HSA21-Si identificirebuli
500 genidan mxolod 425 iqna
aRmoCenili virTagvaSi

• am ubanSi arsebobs rigi

saxeoba specifikuri genebisa

• HSA21-qromosomis genebi
virTagvaSi gafantuia 3
sxvadasxva qromosomaSi, rac
zRudavs yvela geniT
trisomuli virTagvis
miRebis saSualebas
yvelaze saukeTeso ds modelad gamoiyeneben
Ts65Dn-s radgan am modelSi SeimCneva ds–sTvis
damaxasiaTebeli rigi neirologiuri niSnebi :

• anomaliebi dendritebis morfologiaSi

• anomaliebi dendrituli qacvis raodenobaSi
• hi pokampis regionSi neironebis raodenobis Semcireba
• qolinerguli neironebis (qn) degeneracia
• naTxemis moculobis Semcireba
• darRvevebi hi pokampaluri grZelvadiani potenciaciis
ganviTarebaSi
virTagvis modelebi
• Ts65Dn
• Ts1Cje
• Ts1Rhr
• Ts1Yah
• Ts1Yu
 ra doneebze SeiZleba farmakoTerapiuli
samizmeebis gamoyeneba?

• genomis doneze, Seswavla xdeba calkeuli

genebis qve- an zeeqspresirebis gziT

• fenotipur doneze, im neiroanatomiuri an

eleqtrofiziologiuri darRvevebis Seswavlis
xarjze, romelic gamoiwveva daunizmis dros

• molekuluri meqanizmebis doneze, rodesac

Seiswavleba molekuluri meqanizmebis gzebSi
mimdinare is darRvevebi, rac Tavis mxriv ds-s
Camoyalibebas iwvevs
 farmakoTerapiuli samizmeebis gamoyeneba
genomur doneze

Sejvareba nokaut TagvebTan

Ts65Dn Knockout
APP APP APP X =
APP APP

dadebiTi mxare:
izRudeba rigi ujreduli anomaliebisa:
• qolinerguli neironebis degeneracia
• nervis zrdis faqtoris aqsonalur transprtirebasTan dakavSirebuli
darRvevebi
nakli:
• aRdgena xdeba mxolod 60%-iT, rac imis maniSnebelia rom sxva genebsac
aaqvs gavlena mocemul procesebze
• APP - amiloidis
prekursori cila
• wyaroa β-amiloidis
• β-amiloidi akumulirdeba
ujredgare grovebis saxiT
• amcirebs neironuli zrdis
faqtoris retrogradul
transportirebas, rac
iwvevs qolinerguli
neironebis degeneracias
• ainhibirebs NMDA
receptoris aqtivobas
• iwvevs oqsidaciur stress
• auaresebs daswavlisa da
mexsierebis process
 β-amiloidis raodenobis
momatebis mizezebi ds-
iT daavadebulebSi:

1. 21–e qromosomaze ganlagebuli APP–s Sesabamisi genis

trisomiis xarjze, APP-s raodenobis zrda

2. beta sekretaza 2-is zeeqspresiiT- BACE2, romlis Sesabamis

genic aseve 21 qromosomis daunis kritikul regionSia
moTavsebuli.

3. Dyrk1A –trisomiiT, romelic zrdis presenilinis

fosforilirebis xarixs, presenilinis fosforilirebuli
forma ufro stabiluria da zrdis gama sekretazas
aqtivobas, rac sabolood zrdis β-amiloidis raodenobas
 genomur doneze farmakoTerapiuli
samizmeebis gamoyenebis naklovanebebi

1. gasarkvevia ramdeni geni saWiroebs regulirebas

erTsadaimave dros.

2. Sesabamisad gasarkvevi iqneba ramdeni wamali moaxdens

gavlenas maT regulaciaze

3. genebis urTierTgavlenis gamo unda gairkves mocemuli

genebis da maTi Sesabamisi wamlis urTierTgavlenis
efeqti

4. problemas qmnis arsebuli Tagvis modelebis

arasrulfasovneba radgan isini ar Seicaven yvela gens
trisomul mdgomareobaSi
 farmakoTerapiuli samizmeebis gamoyeneba
fenotipur doneze

magaliTi 1:

qolinerguli deficiti, romelic daunizmisas SeimCneva

daswavlisa da mexierebis procesebTan gakavSirebul
darRvevebTanaa kavSirSi

daunizmisas Ts65Dn virTagvebSi

SeiniSneba bazaluri winatvinis
qolinerguli neironebis (bwqn)
degeneracia,
bazaluri winatvinis qolinerguli neironebis (bwqn)
degeneraciis xarisxi izomeba:

1. qolinacetiltransferazas raodenobis SemcirebiT

2. neironuli zrdis faqtoris (nzf) receptoris –

p75-is raodenobis SemcirebiT
(igi gamoiyeneba rogorc markeri)
 1. qolinacetiltransferazas raodenobis
Semcireba

qolinacetiltransferazas
raodenobis klebis problemis
daZleva

acetilqolinesTerazas
inhibireba

izrdeba acetilqolinis
moqmedebis xarisxi postsinafsur
receptorebze
(maTi daSlis Seferxebis xarjze)

rac ds-iT daavadebulebSi zrdis

Semecnebis unarianobas
 qolinacetiltransferazas inhibirebiT
mkurnaloba

• donepezili –acetilqolin esTerazas inhibitori,

iwvevs areSi acetilqolinis raodenobis gazrdas

• ds-iT daavadebul adamianebSi misi gamoyeneba iwvevs

dadebiT gavlenas kognitiur funqciaSi
(ZiriTadad dakavSirebuls metyvelebis procesebTan)
2. neironuli zrdis faqtoris (nzf) receptoris –
p75-is raodenobis SemcirebiT

nzf warmoadgens neirotroful faqtors, romelic

gavlenas axdens centralur da priferul nevul
sistemaSi:

• ujredebis sicocxlisunarianobis gazrdaze,

• maT diferencirebaze
• specifikuri neironebis SenarCunebaze
(maT Sorisa bazaluri winatvinis qolinerguli neironebi)
• aregulirebs im genTa eqspresias, romelic
mniSvnelovania neironuli fenotipisa da ujredis
formis CamoyalibebisaTvis
 hi pokampis neironebSi sinezirebuli nzf ukavSirdeba bazaluri
winatvinis qolinerguli neironebis receptorebs, da endocitozis
Sedegad retrogradulad transportirdeba ujredis sxeulisaken

APP

nzf-is aqsonalur retrogradul transportirebaSi mimdinare

darRvevebi ganapirobebs bazaluri winatvinis qolinerguli
neironebis raodenobis Semcirebas
Tumca bwqn-is raodenobis Semcireba Ts65Dn TagvebSi am neironTa
kvdomiT ki araa ganpirobebuli, aramed p75 genis eqspresiis
qveregulirebiT, romelic regulirdeba nfz signalis xarjze
problemis daZleva:

• nzf-is intracerebroventrikuluri ineqcia 18

Tvian virTagvebSi iwvevs anomaliis daZlevas
da bazaluri winatvinis qolinerguli
neironebis markerebis normaSi dabrunebas
magaliTi 2:

daunizmisas, neironebis degeneracia SeiZleba dakavSirebuli

iyos neiro-anTebiT procesebTan
(iseve rogorc zogierTi sxva neirodegeneraciuli daavadebebisas)
neiro-anTebiTi procesebis done Ts65Dn virTagvebSi
neirodegeneraciuli daavadebebisas, maT Soris
ds-is dros izomeba:

• neiro anTebiTi markerebis saSualebiT

(mag: gliur fibrilaruli mJave cila (GFAP)-(astrocitebSi),

romlis raodenoba ds-s dros klebulobs)
 mkurnalobis gzebi

minociklini
• tetracikluri antibiotikebis ojaxidan
• cximSi xsnadi

mkurnaloba: 6 Tviani Ts65Dn virTagvebis minocikliniT

mkurnalobis Sedegad 75 dRis ganmavlobaSi iwvevs
mexsierebis procesebTan dakavSirebul gaumjobesebebs

minociklinis neiroproteqtuli moqmdeba SesaZloa ganpirobebuli iyos

misi mainhibirebeli moqmedebiT 5 li poqsigenazaze, romelic tvinis
daberebasTan dakavSirebuli anTebis gamomwvevi fermentia

minociklini

ainhibirebs
anTebiTi procesebis
5 li poqsogenaza
gamomwvevi
magaliTi 3:

daunizmisas Ts65Dn virTagvebSi

• P0 stadiaze granularuli ujredebis raodenoba normaSia,
P6 stadiaze SeiniSneba naTxemis granularuli uredebis
deficiti.

naTxemis granularuli ujredebis

deficiti dakavSirebulia:

1.granuraluri ujredebis prekursor

ujredebSi mitozis procesis
intensiobis SemcirebasTan

2.ZuZumwovrebSi organogenezis
ganxorcielebaze pasuxismgebeli
stimulisadmi pasuxis SemcirebasTan
mkurnaloba:
P0 stadiaze SAG 1.1 (organogenezis procesis ganxorcielebis
sinTezuri aqtivatori )–is ineqcia sakmarisia, rom
granularuli ujredebis simkvrive normas daubrundes P6
stadiaze
magaliTi 4:

Ts65Dn virTagvebSi

• Semcirebulia amagznebeli sinafsebis raodenoba,

• normaSia SenarCunebuli mainhibirebeli sinafsebis raodenoba
• gauaresebulia grZelvadiani potenciaciis Camoyalibeba

• GABA receptoris antagonisti – pikrotoqsini –aregulirebs

am disbalanss

• GABA receptoris antagonist-

pentilentetrazoliT - 3 Tvis Ts65Dn
virTagvebis mkurnaloba 30 dRis
ganmavlobaSi, gvaZlevs mexsierebis
procesTan dakavSirebiT gaumjobesebas.
(dozirebis dacva!!!)