Transmissible spongiform encephalopathies (TSE) are a group of rare neurodegenerative diseases which 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. TSE infectivity can cross species barriers and the likelihood that BSE has infected humans in Great Britain underscores the importance of understanding TSE pathogenesis and developing effective anti-TSE therapeutics. The precise nature of the infectious agent of the TSE diseases is unknown. Susceptibility to infection is influenced by the amino acid homology between a normal host protein (PrP-sen) and the abnormal proteinase K-resistant form of this protein, PrP-res. Formation of PrP-res is closely associated with infectivity and PrP-res has been hypothesized to be the infectious agent in the TSE diseases. An understanding of how this protein is made is critical for an understanding of TSE pathogenesis and for devising therapeutic strategies to prevent its synthesis. Our studies address two primary issues in TSE diseases: 1) how differences in the amino acid sequence of PrP-sen and PrP-res influence PrP-res formation, and 2) development of effective therapeutic TSE agents. In particular, we have focused on identifying the structural regions of PrP-sen involved in the species- specific formation of PrP-res and characterizing how mutations in PrP- sen can influence the biochemical characteristics of PrP-sen and the efficiency of PrP-res formation. We have also identified a unique dimeric form of PrP-sen which has led to studies into how changes in transcription and/or translation of PrP can lead to novel forms of the PrP protein. In terms of therapeutic approaches, we are studying how PrP peptides, mutant PrP molecules and a group of compounds known as cyclic tetrapyrroles can inhibit PrP-res formation and/or in vivo disease. - Transmissible spongiform encephalopathies,Scrapie, Prion diseases,PrP,CJD,TSE therapeutics,TSE ,species barriers
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