Prion protein misfolding, strains, and neurotoxicity: An update from studies on mammalian prions

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative disorders affecting humans and other mammalian species. The central event in TSE pathogenesis is the conformational conversion of the cellular prion protein, PrP^C, into the aggregate, β-sheet rich, amyloidogenic form, PrP^Sc. Increasing evidence indicates that distinct PrP^Sc conformers, forming distinct ordered aggregates, can encipher the phenotypic TSE variants related to prion strains. Prion strains are TSE isolates that, after inoculation into syngenic hosts, cause disease with distinct characteristics, such as incubation period, pattern of PrP^Sc distribution, and regional severity of histopathological changes in the brain. In analogy with other amyloid forming proteins, PrP^Sc toxicity is thought to derive from the existence of various intermediate structures prior to the amyloid fiber formation and/or their specific interaction with membranes. The latter appears particularly relevant for the pathogenesis of TSEs associated with GPI-anchored PrP ^Sc, which involves major cellular membrane distortions in neurons. In this review, we update the current knowledge on the molecular mechanisms underlying three fundamental aspects of the basic biology of prions such as the putative mechanism of prion protein conversion to the pathogenic form PrP ^Sc and its propagation, the molecular basis of prion strains, and the mechanism of induced neurotoxicity by PrP^Sc aggregates.