2 PrionsPropertiesSmall, filterable infectious particles that contain protein but no detectable nucleic acid.Prion proteins (PrPC) are encoded by the host genome.PrPC is found in neuronal synapses, binds copper, has unknown function.Prion proteins become infectious and pathogenic (PrPSc) as a result of protein conformational changes.PrPSc can catalyze its own formation from PrPC in animals.PrPSc aggregates and accumulates in diseased brain.
3 PrionsDiseasesChronic, progressive, invariably fatal central nervous system degeneration.Brain pathology is spongiform encephalopathy—large vacuoles in cortex and cerebellum give brain a sponge-like appearance.Affected areas contain microscopic insoluble amyloid fibrils and macrocrystalline arrays known as amyloid plaques.No signs of a host immune response.Can arise spontaneously or by ingestion of infected tissue.Affects wild and domesticated ruminants (sheep and goats: scrapie; cattle: mad cow disease); mink, cats.Experimentally transferred to mice, hamsters, chimpanzees.
4 Prions Distinctive characteristics Proteinaceous infectious agent that contains no nucleic acid and consists only of a single species of protein called PrP.A new kind of infectious agent that can transmit a disease and replicate itself without the intervention of informational nucleic acids.
5 Prions Prions are proteins that cause fatal brain diseases Prion diseases were first detected in domestic ruminantsBSE, mad cow diseaseScrapie in sheep, goatHuman prion diseases can be either inherited or transmitted
7 PrionsThe infectious agent of prion diseases contains protein but no detectable nucleic acidPrPSc is encoded by a host cell geneFig Domains and modifications of the prion protein.
8 Prions Differences between PrPC and PrPSc Proteinase K treatment of PrPSc gives a proteinase-resistant 27–30 kilodalton core fragment (PrP 27–30) (missing N-terminal aa 23-89) that retains infectivityPrPSc tends to form oligomers and aggregates detected as fibrils in infected brainsthe conformational change from PrPC to PrPSc could involve formation of b-helix structure
9 PrionsTop (a) and side views (b), respectively, of PrP 27–30 modeled with theN-terminal portion of the protein as a left-handed b–helix (ribbon arrows displayed in a triangular barrel). The structure of the a-helical part (ribbon helices) was derived from the known strucure of the C-terminal region of PrPC.Fig b-helical model of PrP 27–30.
10 PrionsThe prion hypothesis: formation of infectious and pathogenic prions from normal PrPCPreexisting Prpc is required to propagate infectious prions and cause prin disease
11 Prions Is the prion hypothesis correct? Pathology and diagnosis of prion diseasesTissue abnormalities (insoluble amyloid fifers) of prion disease are confined to CNS
12 Prions Genetics of prion diseases Encoded by a single exon of unique geneHeterozygosity at 129 protects against both inherited and infectious prion diseasePrion diseases are not usually transmitted among different speciesPrion infectivity depends on sequence similarity between donor and recipient prion proteinsBut species barrier is not absolute
13 Prions Strain variation and crossing of the species barrier Human cases of new varient CJD appear to linked to the BSE epidemic in the UKNew varient CJD is distinct from sporadic CJD, caused by different prion strain, less restricted by species barrierProtein pattern of nvCJD is similar to that of BSE-infected animals
14 Prions The nature of the prion infectious agent Prions are transmissible, replicable, and variable disease-causing agents that are distinct from viruses.Whether we define them as “living” or “nonliving” or as an “infectious enzyme,” we do know the following about them:(1) they have arisen in organisms during evolution(2) they are able to propagate themselves and the diseases they cause(3) they appear to be able to evolve and to adapt themselves to different hosts.