Abstract
Prion diseases are a family of transmissible, progressive, and uniformly fatal neurodegenerative disorders that affect humans and animals. Although cross-species transmissions of prions are usually limited by an apparent “species barrier”, the spread of a prion disease to humans by ingestion of contaminated food, or via other routes of exposure, indicates that animal prions can pose a significant public health risk. The infectious agent responsible for the transmission of prion diseases is a misfolded conformer of the prion protein, PrPSc, a pathogenic isoform of the host-encoded, cellular prion protein, PrPC. The detailed mechanisms of prion conversion and replication, as well as the high-resolution structure of PrPSc, are unknown. This review will discuss the general background related to prion biology and assess the structural models proposed to date, while highlighting the experimental challenges of elucidating the structure of PrPSc.
Highlights
The prion protein can exist in multiple isoforms, predominantly the cellular, non-infectious PrPC and the disease-causing PrPSc
The prion protein is most highly expressed in the central nervous system (CNS), but it can be found in other tissues and cell types as well [1,2,3]
Mutations in the Prion Protein Gene (PRNP) gene can cause the development of prion diseases and lead to different clinical phenotypes, including Creutzfeldt-Jakob disease (CJD), GSS and fatal familial insomnia (FFI) [28,29,30]
Summary
The prion protein can exist in multiple isoforms, predominantly the cellular, non-infectious PrPC and the disease-causing PrPSc. The misfolded PrPSc causes the prion diseases, known as transmissible spongiform encephalopathies (TSEs), a group of progressive, neurodegenerative disorders in humans that include kuru [4], Creutzfeldt-Jakob disease (CJD) [5], Gerstmann-Sträussler-Scheinker (GSS) syndrome [6], and fatal familial insomnia (FFI) [7,8]. There are no reported prion disease-associated mutations in either exon 1 or 2, or within any of the introns. A variety of insertion mutations have been found in the octapeptide repeat region. Mutations in the PRNP gene can cause the development of prion diseases and lead to different clinical phenotypes, including CJD, GSS and FFI [28,29,30]. Mutations of the prion protein gene can be classified as: (1) point mutations (i.e., single nucleotide substitutions), which can cause an amino change (missense mutation), can be silent (do not cause alteration in the amino acid sequence), or less commonly can cause the coding to prematurely terminate (stop or nonsense mutation); and (2) insertions and deletions, which are associated with prion diseases
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