Prion Diseases and Neurodegeneration

Prion diseases are neurodegenerative disorders of humans and animals. In humans, the three forms of the prion disease are manifest as infectious, sporadic, and inherited disorders (Table I) (Prusiner 199 1) . Prions cause six transmissible neurodegenerative diseases of animals (Table 2) and four of humans. Prions are composed largely, if not entirely, of an abnormal isoform of the prion protein (PrP) designated Prpsc. Genetic linkage studies of people suffering from prion diseases as well as investigations with transgenic (Tg) mice expressing mutant PrP genes indicate that mutations in human PrP genes cause neurodegeneration. Studies of Tg mice expressing Syrian hamster (SHa) PrP or chimeric SHalmouse (Mo) PrP suggest that an interaction between Prpsc and homolo­ gous Prpc is important in the replication of prions (Prusiner 199 1) . By using these Tg mice, researchers have found the pattern of Prpsc accumulation in brain to be specific for a particular prion isolate. The existence of distinct isolates or strains of prions poses a conundrum, since a wealth of experimental data indicates that prions are devoid of nucleic acid, yet distinct isolates each possess a unique set of properties characterized by the length of the incubation time, distribution of neuropathologic lesions, and pattern of PrpSc accumulation (Dickinson et al 1968, Fraser & Dickinson 1973, Hecker et al 1992, DeArmond et al 1993) . The unique patterns of Prpsc deposition suggest that each prion isolate E a cell-specific trophism that in tum leads to the conversion of PrP into Prpsc within a restricted population of cells. The synthesis of Prpsc is a post-translational process (Borchelt et al