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

## TL;DR

Mice with a specific prion protein mutation are more susceptible to prion disease caused by pure prion protein fibrils.

## Contribution

The study reveals that the E200K mutation increases host susceptibility to protein-only prion fibrils.

## Key findings

- Protein-only PrPSc molecules induce PrPSc formation and brain degeneration in E200K knock-in mice.
- These effects do not occur in mice expressing wild-type prion protein.
- The E200K mutation suggests differences in replication mechanisms between mutant and wild-type prions.

## Abstract

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 (PrPC) into its pathogenic conformer (PrPSc). In contrast, genetic forms of prion diseases are caused by mutations in the PrP sequence that promote mutant PrPSc formation. When reconstituted with either polyanionic or lipid cofactors, purified PrPC substrate can be converted in vitro into PrPSc products that display high levels of specific infectivity when inoculated in WT hosts. In contrast, various protein-only PrPSc molecules formed in the absence of cofactors display much lower levels of specific infectivity. Here, we report that protein-only PrPSc molecules with different sequences can induce the formation of proteinase K-resistant PrPSc 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 PrPSc fibrils, suggesting fundamental differences in the replication mechanisms of WT versus mutant prions.