Biochemistry Of Scrapie Pathogenesis

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Abstract

Transmissible spongiform encephalopathies (TSEs or prion disease) are fatal neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), BSE and chronic wasting disease (CWD). Our project is aimed at understanding and blocking the accumulation of PrP-res, the abnormal form of prion protein (PrP) that appears to underlie TSE transmission and pathogenesis. Using cell culture and cell-free systems we have 1) identified new pyrimidine-based molecules and tetrapyrroles as inhibitors of PrP-res formation, 2) identified regions of PrP-res that are differently folded as a function of TSE strain, 3) determined that the disulfide bonds in PrP-res are intramolecular rather than intermolecular, 4) developed new more physiological membrane vesicle-based PrP conversion reactions, 5)characterized the importance of colocalization of PrP-res and normal PrP in the same membranes for efficient conversion reactions, 6) further characterized the reversibility of PrP-res aggregation, 6)characterized the stimulation of PrP-res formation by heparan sulfate and other sulfated glycans, 7) compared the abilities of various detergents to induce conformational changes and fibril formation in normal PrP that are reminiscent of PrP-res formation.