Mutant knock-in mice display enhanced susceptibility to pure prion protein fibrils

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 <i>in vitro</i> 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.