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13 Cards in this Set
- Front
- Back
Carlton Gajdusek
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-50s
-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 |
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Kuru Disease
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-means trembling in Fore
-uncontrollable tremors throughout body -6-7 months worse -lack coordination -ataxia -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 |
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Spongiform encephalopathy
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-fat filled vacuolisation
-can develop in any mammalian species -some species more prone to spontaneous mutation |
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Creuzfeld-Jakob Disease
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-global
-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 |
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Amyloid type plaques
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-depositions of microfibrils
-some vacuoles full of microfibril protein resemble Alzheimer disease |
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Scrapie disease
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-in sheep
-behaved like infection, transmitted sheep to sheep -2-3 years until symptoms, long incubation period |
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Stanley Prusiner
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-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 |
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PrP
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-prion protein
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Charles Weisman
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-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 |
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PrPc
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-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 |
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PrPsc
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-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 |
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Bovine Spongiform Encephalopathy
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-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 |
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Exogenous PrP proteins
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-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 |