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, PrPC, into the aggregat...

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Bibliographic Details
Published in:International Journal of Cell Biology 2013, Vol.2013 (2013), p.621-644
Main Authors: Poggiolini, Ilaria, Saverioni, Daniela, Parchi, Piero
Format: Article
Language:English
Subjects:
Apoptosis
Creutzfeldt-Jakob disease
Cytokines
Fourier transforms
Genotype & phenotype
Health aspects
Identification and classification
Mammals
Neurodegeneration
Neurotoxicity
Prions
Protein folding
Protein synthesis
Proteins
Review
Spectrum analysis
Spongiform encephalopathies
Studies
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Summary: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, PrPC, into the aggregate, β-sheet rich, amyloidogenic form, PrPSc. Increasing evidence indicates that distinct PrPSc 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 PrPSc distribution, and regional severity of histopathological changes in the brain. In analogy with other amyloid forming proteins, PrPSc 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 PrPSc, 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 PrPSc and its propagation, the molecular basis of prion strains, and the mechanism of induced neurotoxicity by PrPSc aggregates.
ISSN:1687-8876
1687-8884
DOI:10.1155/2013/910314