Prions cause a variety of degenerative neu-rologic diseases that can be infectious, inherited, or sporadic in origin. These dis-eases include scrapie in sheep, bovine spongiform encephalopathy (" mad cow" disease) in cattle, and Creutzfeldt-Jakob dis-ease (CJD), Gerstmann-Straussler-Scheinker (GSS) disease, kuru, and fatal familial insomnia in humans. Prions differ from all other infectious pathogens in that they seem to be devoid of nucleic acid genomes (1); their only known constituent is a protein denoted PrPSc. This protein is an altered version of a normal cellular protein (PrPC) that is encoded by a chromosomal gene (2). PrPc is synthesized in the endoplasmic reticulum, modified in theGolgi apparatus, and transported to the cell surface, where it is bound by a glycophosphatidyl inositol (GPI) anchor (3). Like other GPI-anchored proteins, PrPC appears to reenter the cell through a subcellular compartment bounded by cholesterol-rich, detergent-insoluble membranes (4). Deletion of the GPI addition signal results in greatly diminished synthesis of PrPSc (5). Studies with transgenic mice indicate that PrPc is most efficiently converted into PrPSc when the amino acid sequences of PrPc and PrPSc are identical (6). Mice carrying a mouse PrP transgene with a Pro'02 to Leu mutation (the genetic lesionassociated with GSS disease) develop a neuro-degenerative disorder that is indistinguishable from experimental scrapie, and they produce prionsde novo (7). Overexpres-sion of the mouse wild-type PrP transgene in older mice produces disease characterized by spongiform degeneration of the central nervous system, a necrotizing myopathy involving virtually all skeletal muscle, and a demyelinating peripheral neuropathy (8). Mice in which the wild-type PrP gene has been ablated are resistant to scrapie and do not produce prions, confirming that a source of PrPc is necessary for transmission and pathogenesis of disease (9). How is PrPSc formed? The possibility that it is generated by alternative splicing is unlikely, as the PrPc openreading frame re-