Protease-resistant prion protein produced in vitro lacks detectable infectivity

The 'protein-only' hypothesis of prion propagation argues that infectious prions consist of PrPSc, a conformational isomer of host-derived prion protein (PrPc), which can be distinguished from PrPc by its partial resistance to proteases, While protease-resistant PrP has been produced by mixing PrPSc and recombinant-derived PrPC in vitro, bioassay of any new infectivity has been precluded by the need to use a large molar excess of same species PrPSc. Transgenic mice expressing a chimaeric hamster-mouse PrPC (MH2M PrPC) are, unlike conventional mice, highly susceptible to Sc237 hamster scrapie. In addition, they produce MH2M PrPSc and infectivity which is pathogenic for conventional mice. We have therefore attempted to produce MH2M PrPSc in vitro as any infectivity produced could be distinguished from the hamster PrPSc used to promote the conversion by bioassay in conventional mice. Although protease-resistant MH2M PrP was produced, no infectivity was detected on bioassay, These results argue that acquisition of protease resistance by PrPC is not sufficient for the propagation of infectivity.