PRIONS

Defn: small proteinaceous

infectious particles that resist
inactivation by procedures that
modify viruses and nucleic
acids
 Prion / Amyloid Diseases
Scrapie
Prion Diseases BSE
•High levels of misfolded prion proteins Kuru
•Transmissible Creutzfeldt-Jakob disease

Amyloid Diseases Alzheimer’s (~ 4.5 million, US)

•Amyloid Fibers Found in Brain Parkinson’s (~ 500,000, US)
•Not Transmissible
Huntington’s (~ 30,000 US)

Prion /Amyloid diseases are usually neurodegenerative.

Courtesy of Sid Taylor, MUW
 CJD is a neurological disease

Occurs sporadically in humans at a ratio of 1 per 1 million people

Estimated that 1 per 10,000 people have CJD at the time of death
(estimate could be inaccurate as CJD could be mistaken
for similar neurological diseases)
 Two types of CJD (genetic—
hereditary and infectious)
1. CJD naturally occurring due to a mutation in a gene that encodes
he PrPc neural protein.

2. vCJD infectious caused by consuming beef from cattle with BSE

who are infected with the PrPsc protein

The neural proteins PrPc and PrPsc look different so one can tell the
difference between infectious and hereditary CJD

PrPsc is only transmissible from one human to another via

corneal transplants
brain surgery with contaminated instruments
contaminated brain probes
 CJD--Pathology
Post-mortem examination of brain and neural tissue and
cells show

amyloid (starch-like) protein deposits—plaques between

cells

Non-inflammatory lesions

Strange formations of neurons

Vacuoles—large membrane bound inclusion bodies

 CJD—clinical manifestations
Naturally occurring CJD affects humans at the age of
50-60
vCJD from transmissible prions can affect people
as early as 14

Disease manifestations
shaking
loss of motor control
Dementia—memory loss
paralysis
pneumonia
death—a few months to 1.5 years after first symptoms
 Prion Properties
• Prions are misfolded proteins.
– Prion conformation is rich in -sheets.
• Prions aggregate in amyloids.
• Prions are infectious.
– Prion proteins induce conformational changes in other like proteins.
• Prions can propagate into other cells.

Courtesy of Sid Taylor/MUW

 What are proteins
Proteins are made up of amino acids—each amino acid has its own
Chemical properties

The amino acids are linked together in by peptide bonds to form a

Primary Sequence like “beads on a string”--polypeptide

The primary sequence can form higher ordered structures called

Secondary Structures—these can be alpha helices or beta sheets

Region that has formed secondary structures can fold further to

bring these secondary structures together to form a tertiary structure.

Two or more identical or different tertiary structures come together to

form quaternary structures (more than one subunit)
Formation of a peptide bond
Formation of an alpha helix—
2o structure
Formation of a beta sheet—2o
structure
 Within one chain alpha helices and beta
sheets come together to form a 3o structure—
this can be a functional protein
If more than one tertiary structure form
interactions a 4o structure is formed
Where proteins come from
How proteins are made in
eukaryotic cells
 Where do proteins end up?

1. Stay in the cytoplasm

2. Can be transported to the surface
of the cell—membrane protein
3. Can be secreted from the cell and
into the external milieu
--they may stay near the cells that
secreted them
--they may be circulated throughout the
body
 Summary of previous notes

1. CJD genetic anomaly vs. vCJD caused by consuming cows with

BSE.
2. PrPc (Prion protein cellular), alpha helical makeup, associated with
brain cell surface. Function unknown.
3. PrPsc (Prion protein that looks like protein that causes scrapies
in sheep), beta sheet structure, not associated with the cell surface.
 Summary of previous notes
CJD genetic anomaly in humans

1. PrPc is normally found on the surface of brain cells.

2. In some individuals a rare mutation on chromosome 20 can cause
PrPc to misfold into PrPsc .
3. PrPsc dissociates from the cell membrane but causes PrPc that is
associated with the cell membrane to misfold and dissociate from the
cell surface.
4. As PrPsc dissociates from the cell surface, more PrPc is translated in
brain cell and translocated to the surface/ PrPsc induces misfolding and
release of these proteins. Etcetera.
5. The accumulation of cell free PrPsc forms proteinaceous plaques
between the brain cells
6. Aggregated PrPsc is finally internalized into cells giving cells the
spongiform appearance.
What happens
on a molecular
level ?
 Summary of previous notes
CJD variant CJD from consuming infected beef from cows with BSE

BSE in cattle is analogous to CJD in humans in that it is a genetic

nomaly that leads to misfolding cell associated prion proteins into
athological cell free proteins.
In later stages of the disease process this is manifested as Mad
ow Disease.
The PrPsc from the cow can be transmitted to humans when humans
onsume contaminated meat.
The misfolded protein enters the human’s nerve cells and travels
the brain tissue.
The pathological proteins from the cow causes the PrPc that is
aturally associated with the human cell membrane to misfold
nd dissociate from the cell surface.
 Epidemiology
PrPsc so far only transmissible to man from cows with BSE

Cattle can also transmit disease to domestic cats, sheep and pigs

Transmission from sheep and pigs to humans so far not documented

CWD –chronic wasting disease in elk and muledeer--a disease similar

to BSE in cattle not documented as transmissible to humans

PrPsc—not transmissible through milk or milk products

 Probable cause
Hereditary BSE occurs naturally in cows at a low rate as CJD does
in humans.

1. Cows are butchered before they show manifestations of

disease such that PrPsc enters the human population at a low
rate

2. Can be passed to the offspring and found associated with

placenta that contaminates grass that cows graze on

3. Farmers put ground up cattle in cattle feed, spreading BSE

in the bovine community—PrPsc enters the human population
at a high rate.
 PrPsc is spread from cows with BSE to
humans to cause vCJD by
consumption of such cows

PrPsc has been found concentrated in the following areas in cows

brain
spinal cord
retina (eye)
distal ileum (small intestines)
neurons near the backbone
bone marrow
lymphatic tissue
 Transmission after beef consumption
PrPsc is taken up into Peyer’s patches—(mucousa associated lymphoid
Tissue (AKA MALT)—associated with the small intestines
T-cells induce its uptake by phagocytic calls that do not destroy
the protein
Cells leave MALT and enter the lymphatic tissue where they become
associated with
lymph nodes
spleen
tonsils
Cells can leave the lymphatic system and enter the blood circulatory
system via the thoracic duct
Also lymphatic tissue is highly enervated so PrPsc can enter nerve cells
PrPsc moves up the axon of nerve cells to
spinal cord
eventually the brain
 Route of
transmission:
: MALT to
lymphatic
system
Lymphatic
system to
blood
circulatory
system
 Prevention and Cure
Prevention
1. Don’t feed cows to cows
2. Destroy cow population once BSE found
3. Implement sensitive diagnostic tests to identify cows with
BSE before they show symptoms

There is no good way to destroy PrPsc in living material

Cure

SO FAR NO CURE!!!!

Future treatments might include treatments currently used for

Alzheimer’s Disease.