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Flashcards in Prion Disease Deck (30)
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Describe what prion diseases are?

- Transmissable Spongiform Encephalopathies

- Prion (proteinaceous infectious only)

[No DNA/RNA involved]


List prion diseases for humans

- Creutzfeld-Jakob disease

- Gerstmann-Straüssler-Sheinker syndrome

- Fatal familial insomnia


List prion diseases for animals

- Scrapie]- in sheep

- Bovine spongiform encephalopathy

- Feline spongiform encephalopathy

- Chronic wasting disease]- in elk

- Transmissible mink encephalopathy


Prion diseases relation to sex and age?

M:F equally affected

Age of onset average: 55-75


Neuropathology of Prion disease

- Spongiform change

- Neuronal loss

- Astrogliosis

- Synaptic loss

- Accumulation of PrP


Describe the brain atrophy in prion disease

Global Atrophy:

- enlarged ventricles (hypertrophy)

- widening of sulci

- thinning of gyri


Describe the histological appearance of spongiform change

Cerebral cortex has large numbers of vacuoles]- which itself the spongiform change

Fine filamentous strands passing across vacuoles

Often a motor presentation (cerebellum involved)


Describe the histological appearance of prion protein deposits

Smooth highline inclusion surrounded by neurites, amyloid plaques in cerebellum

Diffuse synaptic staining

Build up around spongiform change


Symptoms of sporadic Creutzfeld-Jakob Disease (CJD)?

- progressive dementia

- typical EEG changes

- motor disturbances

[death within a year]


Investigations for CJD?

- Imaging


- biopsy/autopsy (for diagnosis)


Describe how iatrogenic CJD occurs

Mainly from hormone replacement (seen in France)

Before synthetic hormones, cadaveric pituitaries were used; CJD-containing pituitary + HRT patient -> iatrogentic CJD

[use of cadaveric dura in neurosurgical implants produces a similar effect]


Genes that are linked to genetic causes of CJD?




Features of GSS

- autosomal dominant

- mild dementia

- mean age of death 50 yrs

- lasts 4-5 yrs


Features of FFI

- autosomal dominant

- early sleep disturbance

- neuropsych disease

- late dementia


Features of the prion protein?

Normal cellular protein: PrPc]- expressed in neurons and glia

Chromosome 20 (membrane associated)

We are unsure of its function


Most important codon relating to prion disease?

Codon 129


Relevance of codon 129 in prion disease?


Polymorphism: valine or methionine

Homozygotes (VV/MM)-> greater risk

Heterozygotes (VM) -> less risk

[NB: 50% heterozygous in UK]


Features of PrPp in prion disease

Accumulates in cells and in amyloid deposits

Resistant to degradation by proteinase K

Detectable by ICC (immunocytochemistry)


Difference in PrPc and PrPp amino acid profiles

Exactly the same


Post translational mechanism of prion disease

Normally unfolded protein is in dynamic equilibrium w/ alpha helix form and beta pleated sheet form.

Beta pleated sheet can initiate conformational change in surrounding protein -> seeding -> deposition of insoluble protein (irreversible seeding)


Potential mechanisms for prion disease

- Post-translational modification (altered conformation)

- Mutation in prion gene (in genetic causes)

[NB: PrP knockout mice are immune to PrP infection- must have host protein to convert]


How can prion protein come in different strains?

If you run Western Blot analysis for prion protein, you get 3 molecular weight bands
How many sites are occupied w/ a glycan AND the nature of the glycan explain the variety between strains

[you can map the band patterns to particular strains]


How can we characterise CJD in the lab?

- Codon 129 polymorphism

- Glycotype

- Histotype (spread of pathology)


Evidence of species barrier in prion disease

[transgenic mice express hamster prion protein]

Inoculated (vaccinating) transgenic mice/hamsters with hamster prion protein with hamster prion protein -> scrapie in 75 days

Inoculate wild-type mice w/ hamster prion protein -> no scrapie


What is new variant CJD (vCJD)

Sporadic neuropsychiatric disorder

Linked to bovine spongiform encephalopathy (BSE)

Crossed from cattle population -> humans (endocannibalistic)

Longer duration than CJD

Involves cerebellar ataxia and demenita

ALL PTS ARE 129 MM homozygotes
[pts <45 yrs]


Histological difference between vCJD and CJD

Pathology is much more florid (red/flushed complexion) on vCJD


How could vCJD spread?

Prions in beef cross gut wall -> undergo proliferation in follicular dendritic cells (FDCs) -> taken up by enteric nervous system- via vagus nerve-> medulla


How could protein aggregate pathology spread once vCJD reaches the brain?

- Cell containing abnormal protein dies -> abn protein released into env -> uptake by local cells

- exocytosis and endocytosis by local cells

- transmission via synapses


How to diagnose prion disease in the future?

[prion protein starts to accumulate in lymphoid tissue]

Peripheral lymphoid tissue biopsy


Potential therapeutic approaches for CJD?

[not many available]

- Pentosan polysulphate post exposure as a prophylactic: targets FDC proliferation

- FDC ablation

- beta-sheet breaker peptides

- vaccination?- immune response to protein