Non-genetic propagation of strain-specific properties of scrapie prion protein

Abstract

THE infectious agents causing scrapie and other transmissible spon-giform encephalopathies have been postulated to consist solely of the protease-resistant form of prion protein (PrP^Sc)^1–6. One unprecedented requirement of the protein-only model is that the 'inheritance9 of pathogen strain differences must be mediated by stable variations in PrP^Sc structure^2,7,8, rather than mutations in an agent-specific nucleic acid⁹. Strain differences in PrP^Sc structure have been described for the hyper (HY) and drowsy (DY) strains of hamster transmissible mink encephalopathy (TME)^7,8, a scrapie-like disease originating in mink. Although HY and DY PrP are both post-translationally derived from the precursor prion protein (PrP^c) they are cleaved at different amino-terminal sites by proteinase K (ref. 8). Here we investigate whether this strain-specific property of PrP^Sc is transmitted to PrPc during formation of new PrP^Sc. PrP^Sc from the HY and DY TME strains converted the protease-sensitive PrPc into two distinct sets of protease-resistant PrP products in a cell-free system. These data provide evidence that self-propagation of PrP^Sc polymers with distinct three-dimensional structures could be the molecular basis of scrapie strains.