Exploring the protective roles of prion protein polymorphisms in novel gene targeted mouse models

Introduction: The PRNP ^M129V and the rarer PRNP^G127V polymorphisms are naturally protective against sporadic Creutzfeldt-Jakob disease (sCJD) and prion infection. Heterozygosity at codon 129 of PRNP confers partial protection and reduces sCJD risk, whereas the G127V variant is associated with complete resistance to sCJD and Kuru prion strains in mice, displaying a dominant-negative effect. This rare polymorphism, positively selected during the Kuru epidemic, was found in the heterozygous state among protected individuals.

Objectives: Knock-in mice expressing Prnp ^M128V or Prnp ^G126V were challenged with murine-adapted scrapie strains RML, 22L, and ME7 to assess transmissibility. Transmissibility was evaluated through survival curves, histological analysis, and immunoblotting to assess prion protein glycoform ratios.

Results: As expected, Prnp ^G126V heterozygous mice exhibited prolonged survival and a dominant-negative effect. However, homozygous Prnp ^G126V mice showed strain-dependent transmissibility. While susceptible groups lived significantly longer than wild-type controls, full protection was not observed. In these animals, immunoblotting revealed a shift in glycoform ratios and distinct immunohistochemistry patterns, suggesting structural adaptation of the misfolded protein to overcome an apparent steric barrier. A similar glycoform shift and extended survival were observed in Prnp ^M128V homozygous mice compared to wild-type, although heterozygous Prnp ^M128V mice did not show the same dominant-negative effect seen in G126V heterozygotes.

Conclusion: Both G126V and M128V polymorphisms confer protection against prion disease but via distinct mechanisms, consistent with observations from human PRNP studies. Cryo-EM studies will help determine the structural basis of these adaptation effects.

Funding: Medical Research Council, UK