Distinctive characteristics Prions Properties Diseases Distinctive characteristics

Prions Properties Small, 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.

Prions Diseases Chronic, 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.

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

Prions The infectious agent of prion diseases contains protein but no detectable nucleic acid PrPSc is encoded by a host cell gene Fig. 30.3 Domains and modifications of the prion protein.

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 infectivity PrPSc tends to form oligomers and aggregates detected as fibrils in infected brains the conformational change from PrPC to PrPSc could involve formation of b-helix structure

Prions Top (a) and side views (b), respectively, of PrP 27–30 modeled with the N-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. 30.6 b-helical model of PrP 27–30.

Prions The prion hypothesis: formation of infectious and pathogenic prions from normal PrPC Preexisting Prpc 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

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.

Key Terms Mad cow disease Amyloid New variant Creutzfeldt-Jakob disease (nvCJD or vCJD) Prion Prion disease Quinacrine Scrapie Spongiform encephalopathy Transgene Amyloid BSE Chlorpromazine Creutzfeldt-Jakob disease (CJD) Dendritic cells Dura mater Kuru