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. 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 understanding of TSE pathogenesis and for devising therapeutic strategies to prevent its synthesis. Our studies address three primary issues in TSE diseases at both the molecular and pathogenic level: 1) identifying the important regions in PrP-sen involved in PrP-res formation, 2) development of effective therapeutic TSE agents, and 3) identifying the earliest events which occur during TSE infection. At the molecular level, we have mapped an important amino acid residue involved in the species-specific formation of hamster PrP-res. We have also demonstrated that glycosylation of PrP-sen can significantly influence both species and strain-specific PrP-res generation. We have shown that in PrP-sen beta strands 1 & 2 and alpha helix 1 are important structures for PrP-res formation. Finally, we have recently developed an in vitro tissue culture system which will allow us to study the earliest biochemical events which occur following exposure of cells to TSE infectivity. In terms of therapeutic approaches, we are studying how PrP peptides, anti-oxidants, mutant PrP molecules and cyclic tetrapyrolles can inhibit in vivo disease. We have found that cyclic tetrapyrolles are potent inhibitors of TSE disease in mice and that modifications to the porphyrin ring of the cyclic tetrapyrolles can significantly effect their inhibitory properties.
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