MOLECULAR GENETICS OF SCRAPIE PATHOGENESIS

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Transmissible spongiform encephalopathies (TSE) are a group of neurodegenerative diseases including scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) in cattle. The possibility that the infectious agent which causes BSE may have infected humans in Great Britain underscores the importance of understanding the process which enables the infectious agent of the TSE to cross species barriers. Susceptibility to infection across species barriers 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, which is closely associated with infectivity. Our studies have focused both on identifying the region of PrP-sen involved in the formation of PrP-res and characterizing mutations in PrP and their effect on disease pathogenesis. We have developed an assay in mouse scrapie-infected mouse neuroblastoma cells to model species barrier effects in the conversion of PrP-sen to PrP-res. Using this assay we have shown that, at the level of formation of PrP-res, a single amino acid residue in PrP can control the species barrier between mouse and hamster scrapie. This data suggests that species barriers in the TSE are dependent on interactions between species-specific conformations of PrP molecules. We have assayed PrP-sen mutations associated with familial CJD in uninfected mouse neuroblastoma cells and found that these molecules are more protease-resistant than normal PrP-sen. These data suggest that mutations in PrP-sen may influence the processing of the PrP molecule and predispose certain types of PrP-sen to form PrP-res. Recent data from our lab suggests that multimeric forms of PrP are involved in the conversion of PrP-sen to PrP-res. We previously identified a dimeric form of hamster PrP which has properties intermediate between those of PrP-sen and PrP-res and fulfills many of the properties expected of an intermediate in the conversion process. We have now found that formation of the dimer is controlled at the level of transcription by sequences in the 3' untranslated region of the hamster PrP mRNA and not by the PrP amino acid sequence as expected. Our data suggest that transcriptional control of PrP can generate PrP molecules which resemble PrP-res.