Prion Diseases Flashcards
what is a gene
a heritable unit
what can a prion protein act as
a gene
what are TSEs
transmittable spongiform encephalopathy
what are the 4 prion diseases in man
- Kuru (infectious)
- Creutzfeldt-Jacob Disease (sporadic, inherited, infectious)
- Fatal Familial Insomnia (inherited)
- Gerstmann-Straussler-Sheinker (inherited)
what are prion diseases in other animals
- bovine/feline/mink spongiform encephalopathy
- scrapie
what is Kuru disease?
- trembling with fear
- reported in 1957 - last patient in 2008
fatal neurological disease affected Fore people in highlands of papa new guinea
spread by cannibalistic funeral practices - ate the brains of affected individuals
long incubation period but death within 2 years of presentation
little evidence of dementia
what is CJD
sporadic/iatrogenic cases first described in 1922 (80% of all human TSEs)
inherited ~(15%) infectious (5%)
infectious transmission
what is the triad of CJD neurological changes
- spongiform changes
- neuronal loss
- gliosis (astro and micro)
selective vulnerability (subset of GABAergic neurons)
what do CJD patients get in the brain
‘amyloid’ plaques
if CJD is transmitted via infection , how do prions get from digestive system to brain?
GALT - gut associated lymphoid tissue
from intestine through GALT then to peripheral nerves
what are peyers patches and why are they relevant in CJD
small patches of lymphatic tissue in ileum
folicular dendritic cells in PP is where prions aggregate
M cells also found in PP and take up particulate matter from intestines
how can disease be transmitted genetically AND by infection?
the prion (protein only) hypothesis
Griffiths 1967
what is the prion protein only hypothesis?
the long incubation of prion diseases led to ‘slow virus’ concept
the infectious particle DOES NOT HAVE DNA
- there was no virus and no immune response, UV light, X rays and nucleases did not prevent transmission
what did crystal analysis show about the infectious particle
any associated DNA would be very small
outline the prion protein (PrPc)
highly conserved cell surface protein
expressed in many tissues but high level in neurons
its normal physiological function is unknown (neuronal homeostasis)
what are the 2 forms of PrPc
natural PrPc
infectious PrPsc
outline PrPc (natural)
highly conserved cell surface protein
high level in neurons
GPI-anchor sialoglycoprotein of 33-35kDa
mostly alpha helical
outline PrPsc (infectious)
found as aggregated particles in brain of affected individuals
insoluble in detergents
partially resistant to proteases (VERY hard to break up)
mostly beta-sheet
what gene mutation causes prion disease
Prnp1 gene
very polymorphic and many polymorphic variants
what is the structural difference between the two proteins
PrPc and PrPsc have identical primary sequence but different secondary structure
how does the infectious particle replicate?
by TEMPLATING
PrPsc forms beta sheet
during life inside the cell finds another prion protein that is the normal PrPc, binds and makes it change structure from alpha helical to beta sheet
consequently starts to aggregate
only need one particle to replicate - this happens over and over
how can we test the prion protein hypothesis?
using PrP0/PrP0 viable proteins
1990 experiment showed that injecting infectious prion into normal mouse made it die, but if the mouse did not express PrPc and you injected PrPsc, the nothing happened to the mouse
= this shows the infectious particle has a templating function
what 3 ways can TSEs arise in
infectious
hereditary
spontaneous
there are various strains of PrP - how can we identify them?
they all have the same primary sequence but addition of glycosylation at various sites can cause protease resistance (cut in a different way) which allows for identification
