Prion Disease Flashcards
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
- EEG
- 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?
- GSS
- FFI
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?
RISK FACTOR
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
