Creutzfeldt-Jakob disease and scrapie prions.

Creutzfeldt-Jakob disease, kuru, and Gerstmann-Sträussler syndrome are transmissible degenerative diseases of the central nervous system caused by novel infectious pathogens designated prions. Scrapie is a neurodegenerative disease of sheep and goats and is also caused by prions. Experimental scrapie has been extensively studied in hamsters and mice. The scrapie prion protein (PrPSc) is the only component of the infectious scrapie prion identified, to date. Scrapie infectivity and PrPSc copartition into membranes, rods, and liposomes raising the possibility that only PrPSc might be required for infection; however, a second component such as a small nucleic acid cannot be eliminated. PrPSc is encoded by a single copy cellular gene and not by a hypothetical nucleic acid within purified prion preparations. Normal, uninfected cells express the cellular prion protein (PrPc). Both PrPSc and PrPc appear to be translated from the same 2.1-kb mRNA. The N-terminal amino acid sequences of hamster PrPC and PrPSc are identical; both correspond to that predicted by the translated prion protein (PrP) gene sequence. While the chemical difference between PrPc and PrPSc remains unknown, the organization of the PrP gene argues that it results from a posttranslational event. Six posttranslational modifications of both PrP isoforms have been identified: (1) cleavage of an N-terminal signal peptide, (2) an intramolecular disulfide bond, (3) an N-linked oligosaccharide attached to Asn 181, (4) a second oligosaccharide attached to Asn 197, (5) cleavage of a C-terminal hydrophobic peptide, and (6) a phosphatidylinositol glycolipid attached to the C-terminus. The mouse PrP gene is on chromosome 2 and is linked to a gene controlling the scrapie incubation time (Prn-i). PrP genes from inbred mice with short and long incubation times differ by two amino acids, a finding consistent with but not proving that PrP modulates susceptibility to scrapie. PrPSc stimulation of a posttranslational process which converts PrPc or its precursor into PrPSc is one possible mechanism for prion replication. This is consistent with observations showing that human prion diseases are manifest as infectious, sporadic and genetic disorders.