Prion diseases manifest clinically in three different forms. Sporadic and infectious forms of prion disease are caused by the conversion of WT, cellular prion protein (PrP C ) into its pathogenic conformer (PrP Sc ). In contrast, genetic forms of prion diseases are caused by mutations in the PrP sequence that promote mutant PrP Sc formation. When reconstituted with either polyanionic or lipid cofactors, purified PrP C substrate can be converted in vitro into PrP Sc products that display high levels of specific infectivity when inoculated in WT hosts. In contrast, various protein-only PrP Sc molecules formed in the absence of cofactors display much lower levels of specific infectivity. Here, we report that protein-only PrP Sc molecules with different sequences can induce the formation of proteinase K-resistant PrP Sc molecules and spongiform degeneration in the brains of knock-in mice expressing PrP harbouring the pathogenic E200K mutation, but not in hosts expressing WT PrP. These results indicate that the E200K mutation enhances host susceptibility to various protein-only PrP Sc fibrils, suggesting fundamental differences in the replication mechanisms of WT versus mutant prions.
Walsh et al. (Thu,) studied this question.