3. Prions Disease Flashcards
what are prion diseases
a family of transmissible, neurodegenerative diseases characterised by a long incubation period
what are the 3 forms of prion disease onset
sporadic
acquired
inherited
what does sporadic mean
no obvious underlying cause
name 2 animal prion diseases
scrapie
bovine spongiform encephalitis
name 2 human prion diseases
kuru
Creutzfeldt-Jakob disease
what are the physical symptoms of scrapie
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
who discovered that scrapie was transmissable
Cuille and Chelle (1936)
how did Cuille and Chelle (1936) find scrapie to be infectious
they transmitted it from one sheep to another by intraocular injections of spinal cord
how did bovine spongiform encephalitis emerge
caused by cattle being fed meat and bone meal contaminated with sheep scrapie
how many infected cattle entered the human food chain before it was controlled
500,000
what does the word Kuru mean
trembling
who experienced an epidermic of Kuru
the Fore people in the 1950s in Papua New Guinea
how did Kuru develop in the fore people
ritualistic cannibalism = prion infected material was consumed by members of the tribe
what is the mean incubation period for kuru
12 years - it can be up to 50 years
ritualistic cannibalism was stopped, when was the last reported case?
2005
what is the incidence of CJD
0.5-1 million per year
how has CJD been found to be transmitted, give an example
surgical procedures
human growth hormones extracted from the pituitary of cadavers - administering these to a patient could infect them with prions
CJD can also be transmitted by blood transfusions, why don’t blood banks screen for this?
can only be detected in the blood by PCR, this is beyond blood banks technical capabilities
list some symptoms of CJD
loss of balance
slurred speech
vision problems
abnormal jerking movement
loss of cognition and memory
how long do people with CJD live after symptoms appear, why?
1 year - due to infection caused by immobility
name 2 histopathological features of prion disease
PrP-positive amyloid plaques and scrapie-associated fibrils
gliosis
depletion of neurons and synapses
vacuolation in grey matter and spinal cord
what was scrapie initially thought to be, why
a slow virus - as it takes so long for the properties to manifest, like HIV
what 4 things is scrapie resistant to
- UV and ionising radiation
- nuclease digestion
- heat and autoclaving
- formaldehyde
why is it problematic that scrapie is resistant to formaldehyde
this is used to sterilise surgical instruments
describe the pioneering work that discovered the prion protein led by Stanley prusiner
injected hamsters with scrapie
isolated brain homogenates and did digestion experiments
identified an infectious fraction resistant to digestion by proteinase K
what does prion mean
proteinaceous infectious particle
what are the main structural differences between normal and scrapie prion protein
normal - secondary structure dominated by alpha helices
scrapie - secondary structure dominated by beta-helices
name 2 more differences between normal and scrapie protein
normal = soluble and can be digested by proteases, non-infectious
scrapie = insoluble, highly resistant to digestion by proteases, forms aggregated, infectious
what happens in normal prion protein KO mice
they are resistant to scrapie
describe the model of prion replication
- spontaneous generation of scrapie protein
- scrapie protein transforms endogenous normal PrP into scrapie protein - these molecules accumulate
- scrapie protein enters replication cycle where it is amplified and expanded into a fibril like structure
- these fibrils break into seeds which attract normal prion protein = transformation into PRPsc
where is the Prion protein gene located
chromosome 20
name a polymorphism that makes individuals more susceptible to transformation into PRPsc
M129V
what does the M129V polymorphism also confer
determines the age of onset
what makes variant and sporadic prion disease different
sporadic - symptoms affect the CNS and rapidly decline
variant - symptoms affecting behaviour and emotions will typically develop first
how many classifications of sporadic CJD is there, and what are they dependent on
6 classes
based on Met or Val 129 and molecular weight following protease K digestion
how is variant disease acquired
animal to human - the only form of human prion disease that can do this
how many cases of variant CJD in the Uk
178
who is more likely to be affected by sporadic CJD
older people
who is more likely to be affected by variant CJD
younger people
how is sporadic Prion disease caused
mutations in the open reading frame
RNA editing errors
protein translational errors
describe the studies finding different strains of prions
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
what is the cure for prion disease
there isn’t one!
what are 3 potential avenues for treating prion disease
limit the production of scrapie prion
antibodies or compounds that prevent aggregation
enhancers of autophagy
what two proteins in yeast can exist in either a normal or scrapie form
Sup35
Ure2
what can Sup35 and Ure2 do
can aggregate into amyloid like fibers
