Scrapie is a neurodegenerative disease that can be transmitted to experimental animals. The infectious scrapie agent exhibits many unusual properties which distinguish it from viruses and thus the name """"""""prion"""""""" has been suggested to emphasize these differences. Convergence of many lines of experimental evidence asserts that the scrapie isoform of the prion protein (PrPSc) is a necessary component of the infectious scrapie prion. Six senior investigators with outstanding records of accomplishment in a variety of scientific disciplines and with demonstrated commitments to scrapie research propose to extend their collaborative studies currently supported by an NINDS-Senator Jacob Javits Center for Excellence in Neuroscience. The exciting progress in scrapie research over the past five years coupled with the complementary talents and skills of this group of scientists represent a unique opportunity to make further advances. As described in this application, we want to take advantage of some unprecedented discoveries in prion diseases of animals and humans. Molecular genetic studies in mice and humans have shown that susceptibility to prion diseases - experimental scrapie in mice and Gerstmann-Straussler syndrome (GSS) in humans - is genetically linked to mutations in the open reading frame of the prion protein (PrP) gene. Transgenic (Tg) mice expressing hamster (Ha) PrP genes exhibit susceptibility incubation times and amyloid plaques characteristic of hamsters. Even more significant, these Tg (HaPrP) mice produce HaPrPSc and Ha prions after inoculation with Ha prions. These results have created a transformation in prion research from an area formerly restricted to descriptive and correlative observations to one now amenable to experimental manipulation. We propose to determine if Tg mice harboring a GSS mutant PrP gene will develop scrapie spontaneously. We shall also use Tg mice to identify scrapie domains of HaPrP which are required for synthesis of Ha prion infectivity. Other studies will focus on the nature of scrapie """"""""strains"""""""" as well as a continuing search for a putative scrapie-specific nucleic acid. Learning whether or not mutant PrP molecules are converted into PrPGSS and deposited as amyloid will be important in deciphering the pathogenesis of prion disorders. Recent results suggest that investigations of crystalline arrays of PrPSc may begin to yield useful structural information. Our studies may ultimately elucidate the mechanisms responsible for a variety of CNS degenerative disorders, in particular those of unknown etiology afflicting older people such as Alzheimer's disease.
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