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354: pathobiology > 3. Prions Disease > Flashcards

3. Prions Disease Flashcards

1
Q

what are prion diseases

A

a family of transmissible, neurodegenerative diseases characterised by a long incubation period

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2
Q

what are the 3 forms of prion disease onset

A

sporadic
acquired
inherited

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3
Q

what does sporadic mean

A

no obvious underlying cause

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4
Q

name 2 animal prion diseases

A

scrapie
bovine spongiform encephalitis

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5
Q

name 2 human prion diseases

A

kuru
Creutzfeldt-Jakob disease

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6
Q

what are the physical symptoms of scrapie

A

shepherds would notice healthy animals would lose weight and have difficulty walking, they would find rough surfaces to alleviate the insatiable itching sensation

behavioural symptoms: aggression, locomotor disturbances, tremor, fear

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7
Q

who discovered that scrapie was transmissable

A

Cuille and Chelle (1936)

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8
Q

how did Cuille and Chelle (1936) find scrapie to be infectious

A

they transmitted it from one sheep to another by intraocular injections of spinal cord

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9
Q

how did bovine spongiform encephalitis emerge

A

caused by cattle being fed meat and bone meal contaminated with sheep scrapie

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10
Q

how many infected cattle entered the human food chain before it was controlled

A

500,000

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11
Q

what does the word Kuru mean

A

trembling

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12
Q

who experienced an epidermic of Kuru

A

the Fore people in the 1950s in Papua New Guinea

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13
Q

how did Kuru develop in the fore people

A

ritualistic cannibalism = prion infected material was consumed by members of the tribe

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14
Q

what is the mean incubation period for kuru

A

12 years - it can be up to 50 years

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15
Q

ritualistic cannibalism was stopped, when was the last reported case?

A

2005

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16
Q

what is the incidence of CJD

A

0.5-1 million per year

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17
Q

how has CJD been found to be transmitted, give an example

A

surgical procedures

human growth hormones extracted from the pituitary of cadavers - administering these to a patient could infect them with prions

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18
Q

CJD can also be transmitted by blood transfusions, why don’t blood banks screen for this?

A

can only be detected in the blood by PCR, this is beyond blood banks technical capabilities

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19
Q

list some symptoms of CJD

A

loss of balance
slurred speech
vision problems
abnormal jerking movement
loss of cognition and memory

20
Q

how long do people with CJD live after symptoms appear, why?

A

1 year - due to infection caused by immobility

21
Q

name 2 histopathological features of prion disease

A

PrP-positive amyloid plaques and scrapie-associated fibrils

gliosis

depletion of neurons and synapses

vacuolation in grey matter and spinal cord

22
Q

what was scrapie initially thought to be, why

A

a slow virus - as it takes so long for the properties to manifest, like HIV

23
Q

what 4 things is scrapie resistant to

A
  1. UV and ionising radiation
  2. nuclease digestion
  3. heat and autoclaving
  4. formaldehyde
24
Q

why is it problematic that scrapie is resistant to formaldehyde

A

this is used to sterilise surgical instruments

25
Q

describe the pioneering work that discovered the prion protein led by Stanley prusiner

A

injected hamsters with scrapie
isolated brain homogenates and did digestion experiments
identified an infectious fraction resistant to digestion by proteinase K

26
Q

what does prion mean

A

proteinaceous infectious particle

27
Q

what are the main structural differences between normal and scrapie prion protein

A

normal - secondary structure dominated by alpha helices

scrapie - secondary structure dominated by beta-helices

28
Q

name 2 more differences between normal and scrapie protein

A

normal = soluble and can be digested by proteases, non-infectious

scrapie = insoluble, highly resistant to digestion by proteases, forms aggregated, infectious

29
Q

what happens in normal prion protein KO mice

A

they are resistant to scrapie

30
Q

describe the model of prion replication

A
  1. spontaneous generation of scrapie protein
  2. scrapie protein transforms endogenous normal PrP into scrapie protein - these molecules accumulate
  3. scrapie protein enters replication cycle where it is amplified and expanded into a fibril like structure
  4. these fibrils break into seeds which attract normal prion protein = transformation into PRPsc
31
Q

where is the Prion protein gene located

A

chromosome 20

32
Q

name a polymorphism that makes individuals more susceptible to transformation into PRPsc

A

M129V

33
Q

what does the M129V polymorphism also confer

A

determines the age of onset

34
Q

what makes variant and sporadic prion disease different

A

sporadic - symptoms affect the CNS and rapidly decline

variant - symptoms affecting behaviour and emotions will typically develop first

35
Q

how many classifications of sporadic CJD is there, and what are they dependent on

A

6 classes
based on Met or Val 129 and molecular weight following protease K digestion

36
Q

how is variant disease acquired

A

animal to human - the only form of human prion disease that can do this

37
Q

how many cases of variant CJD in the Uk

A

178

38
Q

who is more likely to be affected by sporadic CJD

A

older people

39
Q

who is more likely to be affected by variant CJD

A

younger people

40
Q

how is sporadic Prion disease caused

A

mutations in the open reading frame
RNA editing errors
protein translational errors

41
Q

describe the studies finding different strains of prions

A

mice injected with prion strain A develop different characteristics to mice injected with prion strain B

  • digesting their brains with proteinase K show distinct patterns of digest on the gel
  • different incubation times, histopathology and targeted neuronal areas
42
Q

what is the cure for prion disease

A

there isn’t one!

43
Q

what are 3 potential avenues for treating prion disease

A

limit the production of scrapie prion
antibodies or compounds that prevent aggregation
enhancers of autophagy

44
Q

what two proteins in yeast can exist in either a normal or scrapie form

A

Sup35
Ure2

45
Q

what can Sup35 and Ure2 do

A

can aggregate into amyloid like fibers

354: pathobiology (10 decks)

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