%0 Journal Article
%T Prion Protein Misfolding, Strains, and Neurotoxicity: An Update from Studies on Mammalian Prions
%A Ilaria Poggiolini
%A Daniela Saverioni
%A Piero Parchi
%J International Journal of Cell Biology
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/910314
%X 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, , into the aggregate, ¦Â-sheet rich, amyloidogenic form, . Increasing evidence indicates that distinct 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 distribution, and regional severity of histopathological changes in the brain. In analogy with other amyloid forming proteins, 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 , 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 and its propagation, the molecular basis of prion strains, and the mechanism of induced neurotoxicity by aggregates. 1. Introduction Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are rapidly progressive neurodegenerative disorders that affect many species of mammals. In humans, they comprise Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), kuru, Gerstmann-Str£¿ussler-Scheinker disease (GSS), and the recently described variably protease-sensitive prionopathy (VPSPr), whereas natural TSEs in animals include scrapie of sheep and goats, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) in deer and elk. Prion diseases belong to the growing group of disorders that are attributed to misfolding and ordered aggregation of proteins, which include Alzheimer¡¯s disease, Parkinson¡¯s disease, systemic amyloidosis, and many others. In prion disease, in particular, the cellular prion protein, , after partial misfolding, converts into a partially protease-resistant disease-associated isoform, , which aggregates in the brain and forms deposits that are associated with the neurodegenerative changes. Distinguishing features of prion diseases among these disorders, however, are their wide
%U http://www.hindawi.com/journals/ijcb/2013/910314/