Alzheimer's disease (AD) is a rapidly growing problem of epidemic proportions. The cause of AD is unknown. The lack of a """"""""perfect"""""""" animal model for AD has slowed progress in deciphering its etiology. While experimental scrapie in animals differs in some respects from AD, many aspects of the CNS degeneration caused by scrapie prions resembles that found in AD. We propose to exploit some recent, 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 (ORF) of the prion protein (PrP) gene. We plan to sequence the ORF's of PrP genes from patients with GSS and familial Creutzfeldt-Jakob disease (FCJD) defining the extent of human PrP gene variation. Additional linkage studies with new PrP gene mutations in families with GSS of FCJD will be undertaken. Sequencing of entire PrP genes from normal humans, patients of GSS, inbred mice with long and short incubation times, sheep breeds with different susceptibilities to scrapie and several species of hamsters with distinct incubation times is planned. A search for prion diseases involving proteins other than PrP is proposed. Grey tremor mice will be examined first since it appears to be both genetic and infectious like GSS. We plan to create physical maps for mice and humans extending about 5 Mb on each side of the PrP gene. YAC clones will be recovered and used to construct contig maps. Probes derived from these YAC clones will be employed to identify a linked scrapie incubation time gene (Prn-i) in mice and the GSS gene in humans if these prove to be separable from the PrP gene. We plan to identify PrP related genes in mammals and in lower organisms especially those amenable to genetic manipulation. As more is learned about prion diseases it may be possible to determine whether natural scrapie is a genetic or infectious disease - both mechanisms have been proposed. We plan a set of genetic linkage studies in sheep with scrapie. Random mutagenesis of PrP genes from rodents will be performed and expressed clones assessed for production of PrPSc and infectivity. Such studies may ultimately elucidate the mechanisms underlying diseases which are both infectious and genetic. Indeed, unprecedented discoveries in studies on prion diseases signal new directions in CNS degenerative disease research;the implications for Alzheimer's disease and some other neurodegenerative disorders of older people may be profound.
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