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NMH: Module 2 > Prion Disease > Flashcards

Prion Disease Flashcards

1
Q

Describe what prion diseases are?

A
  • Transmissable Spongiform Encephalopathies
  • Prion (proteinaceous infectious only)

[No DNA/RNA involved]

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2
Q

List prion diseases for humans

A
  • Creutzfeld-Jakob disease
  • Gerstmann-Straüssler-Sheinker syndrome
  • Fatal familial insomnia
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3
Q

List prion diseases for animals

A
  • Scrapie]- in sheep
  • Bovine spongiform encephalopathy
  • Feline spongiform encephalopathy
  • Chronic wasting disease]- in elk
  • Transmissible mink encephalopathy
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4
Q

Prion diseases relation to sex and age?

A

M:F equally affected

Age of onset average: 55-75

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5
Q

Neuropathology of Prion disease

A
  • Spongiform change
  • Neuronal loss
  • Astrogliosis
  • Synaptic loss
  • Accumulation of PrP
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6
Q

Describe the brain atrophy in prion disease

A

Global Atrophy:

  • enlarged ventricles (hypertrophy)
  • widening of sulci
  • thinning of gyri
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7
Q

Describe the histological appearance of spongiform change

A

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

Fine filamentous strands passing across vacuoles

Often a motor presentation (cerebellum involved)

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8
Q

Describe the histological appearance of prion protein deposits

A

Smooth highline inclusion surrounded by neurites, amyloid plaques in cerebellum

Diffuse synaptic staining

Build up around spongiform change

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9
Q

Symptoms of sporadic Creutzfeld-Jakob Disease (CJD)?

A
  • progressive dementia
  • typical EEG changes
  • motor disturbances

[death within a year]

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10
Q

Investigations for CJD?

A
  • Imaging
  • EEG
  • biopsy/autopsy (for diagnosis)
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11
Q

Describe how iatrogenic CJD occurs

A

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]

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12
Q

Genes that are linked to genetic causes of CJD?

A
  • GSS

- FFI

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13
Q

Features of GSS

A
  • autosomal dominant
  • mild dementia
  • mean age of death 50 yrs
  • lasts 4-5 yrs
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14
Q

Features of FFI

A
  • autosomal dominant
  • early sleep disturbance
  • neuropsych disease
  • late dementia
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15
Q

Features of the prion protein?

A

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

Chromosome 20 (membrane associated)

We are unsure of its function

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16
Q

Most important codon relating to prion disease?

A

Codon 129

17
Q

Relevance of codon 129 in prion disease?

A

RISK FACTOR

Polymorphism: valine or methionine

Homozygotes (VV/MM)-> greater risk

Heterozygotes (VM) -> less risk

[NB: 50% heterozygous in UK]

18
Q

Features of PrPp in prion disease

A

Accumulates in cells and in amyloid deposits

Resistant to degradation by proteinase K

Detectable by ICC (immunocytochemistry)

19
Q

Difference in PrPc and PrPp amino acid profiles

A

Exactly the same

20
Q

Post translational mechanism of prion disease

A

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)

21
Q

Potential mechanisms for prion disease

A
  • 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]

22
Q

How can prion protein come in different strains?

A

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]

23
Q

How can we characterise CJD in the lab?

A
  • Codon 129 polymorphism
  • Glycotype
  • Histotype (spread of pathology)
24
Q

Evidence of species barrier in prion disease

A

[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

25
Q

What is new variant CJD (vCJD)

A

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]

26
Q

Histological difference between vCJD and CJD

A

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

27
Q

How could vCJD spread?

A

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

28
Q

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

A
  • Cell containing abnormal protein dies -> abn protein released into env -> uptake by local cells
  • exocytosis and endocytosis by local cells
  • transmission via synapses
29
Q

How to diagnose prion disease in the future?

A

[prion protein starts to accumulate in lymphoid tissue]

Peripheral lymphoid tissue biopsy

30
Q

Potential therapeutic approaches for CJD?

A

[not many available]

  • Pentosan polysulphate post exposure as a prophylactic: targets FDC proliferation
  • FDC ablation
  • beta-sheet breaker peptides
  • vaccination?- immune response to protein

NMH: Module 2 (33 decks)

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