THE infectious agents causing scrapie and other transmissible spongifo
rm encephalopathies have been postulated to consist solely of the prot
ease-resistant form of prion protein (PrPSc)(1-6). One unprecedented r
equirement of the protein-only model is that the 'inheritance' of path
ogen strain differences must be mediated by stable variations in PrPSc
structure(2,7,8), rather than mutations in an agent-specific nucleic
acid(9). Strain differences in PrPSc structure have been described for
the hyper (HY) and drowsy (DY) strains of hamster transmissible mink
encephalopathy (TME)(7,8), a a scrapie-like disease originating in min
k. Although HY and DY PrPSc are both post-translationally derived from
the precursor prion protein (PrPc) they are cleaved at different amin
o-terminal sites by proteinase K (ref. 8). Here we investigate whether
this strain-specific property of PrPSc is transmitted to PrPc during
formation of new PrPSc. PrPSc from the HY and DY TME strains converted
the protease-sensitive PrPc into two distinct sets of protease-resist
ant PrP products in a cell-free system. These data provide evidence th
at self-propagation of PrPSc polymers with distinct three-dimensional
structures could be the molecular basis of scrapie strains.