Prions cause transmissible and genetic neurodegenerative diseases including scrapie and bovine spongiform encephalopathy of animals and Creutzfeldt- Jakob disease and Gerstmann-Straussler-Scheinker syndrome (GSS) of humans. Infectious prion particles are composed largely, if not entirely, of an abnormal isoform of the prion protein (PrP) which is encoded by a chromosomal gene. A post-translational process, as yet unidentified, converts cellular PrP into the abnormal isoform. Transgenic (Tg) mice expressing hamster (Ha) PrP genes exhibit susceptibility, incubation times, amyloid plaques and prion biosynthesis characteristic of hamsters after inoculation with Ha scrapie prions. Point mutations in PrP genes of animals and humans are genetically linked to development of neurodegeneration. Molecular genetic studies in mice and humans have shown that susceptibility to prion diseases - experimental scrapie in mice and GSS in humans - is genetically linked to mutations in the open reading frame of the PrP gene. Tg mice expressing mutant PrP of GSS spontaneously develop neurologic dysfunction and spongiform neuropathology; whether brain extracts from these mice will produce CNS disease after inoculation into animals is under investigation. Many observations argue that prions are novel infectious pathogens and distinct from both viruses and viroids. Five senior investigators with outstanding records of accomplishment in a variety of scientific disciplines and with demonstrated commitments to scrapie research propose to continue and extend their collaborative studies. 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. Tg mice expressing foreign PrP genes 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 shall use Tg mice to identify domains of HaPrP which are required for synthesis of Ha prion infectivity. Other studies will focus on the nature of scrapie """"""""strains"""""""" and control of scrapie incubation times. Some of the proposed investigations will focus on the secondary and tertiary structure of PrP and a PrP domain that determines its topology. 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.
