Abstract
Prion diseases are a unique group of rare neurodegenerative disorders characterized by tissue deposition of heterogeneous aggregates of abnormally folded protease-resistant prion protein (PrPSc), a broad spectrum of disease phenotypes and a variable efficiency of disease propagation in vivo. The dominant clinicopathological phenotypes of human prion disease include Creutzfeldt–Jakob disease, fatal insomnia, variably protease-sensitive prionopathy, and Gerstmann–Sträussler–Scheinker disease. Prion disease propagation into susceptible hosts led to the isolation and characterization of prion strains, initially operatively defined as “isolates” causing diseases with distinctive characteristics, such as the incubation period, the pattern of PrPSc distribution, and the regional severity of neuropathological changes after injection into syngeneic hosts. More recently, the structural basis of prion strains has been linked to amyloid polymorphs (i.e., variant amyloid protein conformations) and the concept extended to all protein amyloids showing polymorphic structures and some evidence of in vivo or in vitro propagation by seeding. Despite the significant advances, however, the link between amyloid structure and disease is not understood in many instances. Here we reviewed the most significant contributions of human prion disease studies to current knowledge of the molecular basis of phenotypic variability and the prion strain phenomenon and underlined the unsolved issues from the human disease perspective.
Highlights
Prion diseases, known as transmissible spongiform encephalopathies (TSEs), belong to a group of neurodegenerative disorders of humans and animals, characterized by aggregation and tissue deposition of a misfolded form of the prion protein (PrP)
The demonstration that, in both Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker disease (GSS) [26,27,28], PrPSc molecules with distinct physicochemical properties correlate with distinct clinicopathological disease variants that are independent of the prion protein gene (PRNP) genotype laid the foundation for the first robust classification of the disease and the subsequent characterization of human prion strains by transmission studies
The calculated incidence of sporadic CJD (sCJD) cases with the co-occurrence of PrPSc types varied from 12% to 44% among studies that used standard antibodies against PrP C-terminus [45,46,47,48,49,50], but increased to 100% in those that used antibodies, thought to be selective for type 1, that recognize an epitope between residues 82 and 96, which is cleaved off by proteinase K (PK) in type 2 PrPSc
Summary
Known as transmissible spongiform encephalopathies (TSEs), belong to a group of neurodegenerative disorders of humans and animals, characterized by aggregation and tissue deposition of a misfolded form of the prion protein (PrP). In this pathological process, the physiological cellular PrP (PrPC ) converts into abnormal PrP (PrPSc ) through post-translational events that lead to an increased β-sheet conformation [1]. Prion diseases include a wide range of clinicopathological phenotypes They often propagate after inoculation into susceptible hosts, a property that led to the isolation and characterization of different prion strains. We have reviewed the most significant contributions of studies on human prion diseases to current knowledge of the molecular basis of phenotypic variability and the prion strain phenomenon and underlined the unsolved issues from the human disease perspective
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