Our broad, long-term objectives are to address the etiologies and mechanisms of prion diseases with particular emphasis on interspecies transmission. These issues are intimately linked to how prion strains are enciphered by different prion protein (PrP) conformations, which remains a significant challenge for the prion hypothesis. The occurrence of variant human Creutzfeldt Jakob disease as a result of exposure to bovine spongiform encephalopathy (BSE) raises concern over the emergence and zoonotic potential of chronic wasting disease (CWD) of cervids, as well as atypical scrapie, a recently-recognized and surprisingly prevalent prion disease of sheep. The demonstration that the most recent US case of BSE occurred in a cow expressing a PrP mutation corresponding to the most common familial CJD mutation, raises questions about the origins and pathogenesis of BSE and other prion diseases. In our lead aim we hypothesize that the PrP E211K mutation is associated with the spontaneous development of bovine prions and propose to address this, and alternate possibilities, using Tg mouse models;we also propose to develop and characterize Tg mouse models in which to study the pathogenesis of atypical scrapie. The underlying hypothesis supporting aim 2 is that interspecies prion transmission is governed by the conformational compatibility between PrPSc in a given strain and PrPC expressed in a new host. We propose to accelerate studies of interspecies transmission by combining Tg mouse and PMCA technologies and to determine the ability of various prion strains to convert different PrP primary structures, with particular emphasis on the transmission potential of distinct CWD strains and atypical scrapie prions in humans. In our final aim, we hypothesize that mutations affecting endoproteolytic cleavage of PrP alter the strain-dependent properties of PrPSc and result in prions with new strain properties. Compelling support for this notion comes not only from artificially mutated versions of PrP, but also from the effects of naturally-occurring cervid PrP polymorphisms on CWD pathogenesis and strain propagation. We anticipate that the proposed studies will provide important information about basic mechanisms of prion propagation, prion species barriers, the evolution of new prion strains, and the means by which prions propagate strain information that will be crucially important for controlling or preventing future epidemics of fatal neurodegerative prion diseases.
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