Scrapie-associated fibrils, PrP protein and the Sinc gene.

Scrapie-associated fibrils (SAF) are disease-specific structures found in extracts of the brains of animals affected with scrapie. These structures are pathological aggregates of a normal host protein called PrP. In collaboration with Konrad Beyreuther (Heidelberg), we have characterized the multiple forms of PrP found in SAF fractions from mouse brain affected by the ME7 strain of scrapie. There is no in vivo N-terminal cleavage of the most abundant forms of PrP. However, N-terminal cleavage of some minor forms of PrP does occur in vivo within a domain of repetitive sequences at sites similar to but distinct from those cut by proteinase K in vitro. We suggest that such covalently modified forms of PrP may be the result of enzymic degradation occurring as a consequence rather than as a cause of disease. We also found a novel, as yet unidentified, amino acid derivative of the arginine residue at position 3 in both hamster and mouse PrP 33-35, which may predispose PrP to form SAF. Carlson and colleagues have discovered a linkage between the PrP gene and the murine gene provisionally called Prn-i which, from the work of Carp and coworkers, appears identical to the Sinc gene. The Sinc gene is the major gene determining the incubation period of all strains of scrapie in mice. We have evidence for a linkage of the PrP gene and Sinc using inbred mice of known Sinc genotype, including VM(Sincp7) and VM(Sincs7) congenic mice. PrP may even be the protein product of the Sinc gene.