MOLECULAR GENETICS OF SCRAPIE PATHOGENESIS

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Transmissible spongiform encephalopathies (TSE) are a group of rare neurodegenerative diseases including scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) in cattle. The infectious agent of the TSE can cross species barriers and the likelihood that BSE has infected humans in Great Britain underscores the importance of understanding TSE pathogenesis. 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 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 have focused on identifying the structural regions of PrP-sen involved in the formation of PrP-res, characterizing how mutations in PrP-sen can influence both the characteristics of PrP-sen and the efficiency of PrP-res formation, and how changes in transcription and/or translation of PrP can lead to novel forms of the PrP protein.