Properties Small, filterable infectious particles that contain protein but no detectable nucleic acid. Prion proteins (PrP C ) are encoded by the host genome. PrP C is found in neuronal synapses, binds copper, has unknown function. Prion proteins become infectious and pathogenic (PrP Sc ) as a result of protein conformational changes. PrP Sc can catalyze its own formation from PrP C in animals. PrP Sc aggregates and accumulates in diseased brain. Prions
Diseases Chronic, progressive, invariably fatal central nervous system degeneration. Brain pathology is spongiform encephalopathylarge 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. 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. Prions
Prions are proteins that cause fatal brain diseases Prion diseases were first detected in domestic ruminants BSE, mad cow disease Scrapie in sheep, goat Human prion diseases can be either inherited or transmitted Prions
The infectious agent of prion diseases contains protein but no detectable nucleic acid PrP Sc is encoded by a host cell gene Prions Fig Domains and modifications of the prion protein.
Differences between PrP C and PrP Sc Proteinase K treatment of PrP Sc gives a proteinase-resistant 27–30 kilodalton core fragment (PrP 27–30) (missing N-terminal aa 23-89) that retains infectivity PrP Sc tends to form oligomers and aggregates detected as fibrils in infected brains the conformational change from PrP C to PrP Sc could involve formation of -helix structure Prions
Fig helical model of PrP 27–30. Top (a) and side views (b), respectively, of PrP 27–30 modeled with the N-terminal portion of the protein as a left-handed –helix (ribbon arrows displayed in a triangular barrel). The structure of the - helical part (ribbon helices) was derived from the known strucure of the C-terminal region of PrP C.
The prion hypothesis: formation of infectious and pathogenic prions from normal PrP C Preexisting Prp c is required to propagate infectious prions and cause prin disease Prions
Is the prion hypothesis correct? Pathology and diagnosis of prion diseases Tissue abnormalities (insoluble amyloid fifers) of prion disease are confined to CNS Prions
Genetics of prion diseases Encoded by a single exon of unique gene Heterozygosity at 129 protects against both inherited and infectious prion disease Prion diseases are not usually transmitted among different species Prion infectivity depends on sequence similarity between donor and recipient prion proteins But species barrier is not absolute
Prions Strain variation and crossing of the species barrier Human cases of new varient CJD appear to linked to the BSE epidemic in the UK New varient CJD is distinct from sporadic CJD, caused by different prion strain, less restricted by species barrier Protein pattern of nvCJD is similar to that of BSE- infected animals
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. Prions
Key Terms Amyloid BSE Chlorpromazine Creutzfeldt-Jakob disease (CJD) Dendritic cells Dura mater Kuru Mad cow disease New variant Creutzfeldt-Jakob disease (nvCJD or vCJD) Prion Prion disease Quinacrine Scrapie Spongiform encephalopathy Transgene