3. Prions Disease

Question 1

what are prion diseases

Answer 1

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

Question 2

what are the 3 forms of prion disease onset

Answer 2

sporadic
acquired
inherited

Question 3

what does sporadic mean

Answer 3

no obvious underlying cause

Question 4

name 2 animal prion diseases

Answer 4

scrapie
bovine spongiform encephalitis

Question 5

name 2 human prion diseases

Answer 5

kuru
Creutzfeldt-Jakob disease

Question 6

what are the physical symptoms of scrapie

Answer 6

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

Question 7

who discovered that scrapie was transmissable

Answer 7

Cuille and Chelle (1936)

Question 8

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

Answer 8

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

Question 9

how did bovine spongiform encephalitis emerge

Answer 9

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

Question 10

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

Answer 10

500,000

Question 11

what does the word Kuru mean

Answer 11

trembling

Question 12

who experienced an epidermic of Kuru

Answer 12

the Fore people in the 1950s in Papua New Guinea

Question 13

how did Kuru develop in the fore people

Answer 13

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

Question 14

what is the mean incubation period for kuru

Answer 14

12 years - it can be up to 50 years

Question 15

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

Answer 15

2005

Question 16

what is the incidence of CJD

Answer 16

0.5-1 million per year

Question 17

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

Answer 17

surgical procedures

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

Question 18

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

Answer 18

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

Question 19

list some symptoms of CJD

Answer 19

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

Question 20

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

Answer 20

1 year - due to infection caused by immobility

Question 21

name 2 histopathological features of prion disease

Answer 21

PrP-positive amyloid plaques and scrapie-associated fibrils

gliosis

depletion of neurons and synapses

vacuolation in grey matter and spinal cord

Question 22

what was scrapie initially thought to be, why

Answer 22

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

Question 23

what 4 things is scrapie resistant to

Answer 23

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

Question 24

why is it problematic that scrapie is resistant to formaldehyde

Answer 24

this is used to sterilise surgical instruments

Question 25

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

Answer 25

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

Question 26

what does prion mean

Answer 26

proteinaceous infectious particle

Question 27

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

Answer 27

normal - secondary structure dominated by alpha helices scrapie - secondary structure dominated by beta-helices

Question 28

name 2 more differences between normal and scrapie protein

Answer 28

normal = soluble and can be digested by proteases, non-infectious scrapie = insoluble, highly resistant to digestion by proteases, forms aggregated, infectious

Question 29

what happens in normal prion protein KO mice

Answer 29

they are resistant to scrapie

Question 30

describe the model of prion replication

Answer 30

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

Question 31

where is the Prion protein gene located

Answer 31

chromosome 20

Question 32

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

Answer 32

M129V

Question 33

what does the M129V polymorphism also confer

Answer 33

determines the age of onset

Question 34

what makes variant and sporadic prion disease different

Answer 34

sporadic - symptoms affect the CNS and rapidly decline variant - symptoms affecting behaviour and emotions will typically develop first

Question 35

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

Answer 35

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

Question 36

how is variant disease acquired

Answer 36

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

Question 37

how many cases of variant CJD in the Uk

Answer 37

178

Question 38

who is more likely to be affected by sporadic CJD

Answer 38

older people

Question 39

who is more likely to be affected by variant CJD

Answer 39

younger people

Question 40

how is sporadic Prion disease caused

Answer 40

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

Question 41

describe the studies finding different strains of prions

Answer 41

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

Question 42

what is the cure for prion disease

Answer 42

there isn't one!

Question 43

what are 3 potential avenues for treating prion disease

Answer 43

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

Question 44

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

Answer 44

Sup35 Ure2

Question 45

what can Sup35 and Ure2 do

Answer 45

can aggregate into amyloid like fibers