18-2 |
Prion diseases and their mechanisms |
S. A. PRIOLA, National Institute of Allergy & Infectious Diseases, National Institutes of Health, 903 S. 4th St., Hamilton, MT 59840 Transmissible spongiform encephalopathies (TSE) or prion diseases are a group of rare but uniformly fatal neurodegenerative diseases that include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease (CWD) in mule deer and elk. The fact that BSE has crossed species barriers and infected humans in Great Britain underscores the importance of understanding TSE pathogenesis and developing effective TSE diagnostics and therapeutics. Research into the mechanisms involved in TSE disease has been complicated by the fact that the precise nature of the infectious agent of these diseases is unknown. No virus or bacteria has ever been associated with TSE infectivity. However, susceptibility to infection can be influenced by amino acid homology between a normal host protein (PrP-sen) and an abnormal, TSE-specific form of this protein, PrP-res. Formation of PrP-res is closely associated with infectivity and PrP-res itself has been suggested to be the hypothesized "protein-only" infectious agent of the TSE diseases. Although this hypothesis has yet to be definitively proven, the importance of PrP in TSE pathogenesis is undeniable. Several studies have now clearly demonstrated that PrP-res can faithfully replicate itself by using normal host PrP-sen as a template, a process that is strongly influenced by the primary sequence of PrP. These studies provide a molecular basis for the transmission of TSE infectivity across species barriers as well as susceptibility to TSE disease, both of which are strongly influenced by PrP amino acid sequence. Research into the molecular mechanisms that underlie the TSE infectious process combined with research into basic TSE pathogenesis have led to the identification of new diagnostic approaches for the early detection of TSE infection as well as new inhibitors of TSE disease.
Session 18, The prion diseases: Human health and food safety
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