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Carlton Gajdusek
-went to Papua-New Guinea, stayed with tribe called Fore
-tribe had Kuru disease
-speculated disease due to infection, even though no inflammation
-inoculated, gave up, heard of Scrapie, double checked
-initially called it a slow virus
Kuru Disease
-means trembling in Fore
-uncontrollable tremors throughout body
-6-7 months worse
-lack coordination
-trouble walking
-dementia and loss cognitive functions
-death rate 100%
-spongiform encephalopathy found in their brain
-caused neurons to degenerate and replaced with fat filled vacuoles
-appeared identical to CJD
-not genetic because death rate was askew
-no inflammation, difficult working out what caused infection
Spongiform encephalopathy
-fat filled vacuolisation
-can develop in any mammalian species
-some species more prone to spontaneous mutation
Creuzfeld-Jakob Disease
-trembling, loss coordination, dementia
-1/2 million/year
-cell inclusions and vacuoles get deposition of microfibrils
-human families higher incidence of disease due to misfolding due to mutations in PrPc genes
-new variant: affects young more than old, shorter incubation, psychiatric manifestation, not trembling at first, region of brain infected is different
-glycosylation and folding of CJD PrP more similar to PrPsc and new varient CJD PrP more similar to PrP BSE
Amyloid type plaques
-depositions of microfibrils
-some vacuoles full of microfibril protein resemble Alzheimer disease
Scrapie disease
-in sheep
-behaved like infection, transmitted sheep to sheep
-2-3 years until symptoms, long incubation period
Stanley Prusiner
-mice not good lab species
-put scrapie from sheep into hamster brains, developped spongiform encephalopathy in 6 weeks
-pratical investigation
-fractionated infected brain into membrane, non-membrane, protein, lipid, nucelic acid
-infected brains had extra band of protein on gels
-no nucleic acid in brain equal to virus genome
-speculated new infectious protein
-destroyed protein, destroyed infectivity
-called extra protein a prion protein
-prion protein
Charles Weisman
-purified Scrapie Prp, found aa sequence
-reverse transcribed to get nucleotide sequence, made into synthetic oligonucleotide sequences, probe wehre prion protein encoded
-encoded by genome of host mammalian species
-PrP cellular gene
-expressed in lymphatic tissues, monocytes, intestinal epithelial and neurons
-more alpha helices
-alpha helical protein more soluble
-function unclear
-if not expressed, indistinguishable from those without it knocked out
-surface glycoprotein
-exists at certain homeostatic concentrations
-folds in right conformation, rare misfolding in neuron
-different MW, different glycosylation pattern
-missing some aa on its end
-different tertiary structure
-more beta sheets, less soluble
-mis-folded post-translationally modified PrPc
-precipitates out of cells and forms microfibrillar agregates and plaques (toxic)
-effects PrPc by enzymatic or crystallisation nucleation effect (induced PrPc to misfold and turn into PrPsc)
-levels PrPc drop below homeostatic, cell makes more PrPc genes, become PrPsc
-toxicity kills cell
-in lymphatic tissues, monocytes, intestinal epithelial process is so slow, time to kill cell longer than cell's half life
-neurons do not replicate, so affected by PrPsc, takes a while for infection
Bovine Spongiform Encephalopathy
-cows not more prone, never before 1990s
-slaughter animals, use high pressure hoses to separate fat and protein from bone with organic solvent
-PrPsc goes with fatty membranes
-fat prices descrease, stopped using organic solvents to cut costs
-fragments now had proteins and fat in animal feed
-PrPsc in cattle feed, very inefficient at cuasing misfolding in cow or human PrP (from sheep)
-huge about PrPsc, so PrP BSE occured (by misfolding)
-higher efficiency misfolding of human protein
-got into human diet as new variant Creuzfeld-Jakob disease
Exogenous PrP proteins
-get into brain and cause disease
-if ingested affects lymphocytes and monocytes which circulate and get to brain to become glial cells
-can get PrPsc this way, too

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