Heterozygosity for cervid S138N polymorphism results in subclinical CWD in gene-targeted mice and progressive inhibition of prion conversion

Author:

Arifin Maria I.1ORCID,Kaczmarczyk Lech2ORCID,Zeng Doris1ORCID,Hannaoui Samia1,Lee Chi1,Chang Sheng Chun1,Mitchell Gordon3ORCID,McKenzie Debbie4ORCID,Beekes Michael5ORCID,Jackson Walker2,Gilch Sabine1ORCID

Affiliation:

1. Faculty of Veterinary Medicine and Hotchkiss Brain Institute, University of Calgary, Alberta T2N 4Z6, Canada

2. Department of Clinical and Experimental Medicine, Wallenberg Center for Molecular Medicine, Linköping University, Linköping 581 83, Sweden

3. National and World Organisation for Animal Health Reference Laboratory for Scrapie and Chronic Wasting Disease, Canadian Food Inspection Agency, Ontario K1A 0Y9, Canada

4. Department of Biological Sciences and Centre for Prions and Protein Folding Diseases, University of Alberta, Alberta T6G 2M8, Canada

5. Prion and Prionoid Research Unit, Centre for Biological Threats and Special Pathogens, Robert Koch Institute, Berlin 13353, Germany

Abstract

Prions are proteinaceous infectious particles that replicate by structural conversion of the host-encoded cellular prion protein (PrP C ), causing fatal neurodegenerative diseases in mammals. Species-specific amino acid substitutions (AAS) arising from single nucleotide polymorphisms within the prion protein gene ( Prnp ) modulate prion disease pathogenesis, and, in several instances, reduce susceptibility of homo- or heterozygous AAS carriers to prion infection. However, a mechanistic understanding of their protective effects against clinical disease is missing. We generated gene-targeted mouse infection models of chronic wasting disease (CWD), a highly contagious prion disease of cervids. These mice express wild-type deer or PrP C harboring the S138N substitution homo- or heterozygously, a polymorphism found exclusively in reindeer ( Rangifer tarandus spp. ) and fallow deer ( Dama dama ). The wild-type deer PrP-expressing model recapitulated CWD pathogenesis including fecal shedding. Encoding at least one 138N allele prevented clinical CWD, accumulation of protease-resistant PrP (PrP res ) and abnormal PrP deposits in the brain tissue. However, prion seeding activity was detected in spleens, brains, and feces of these mice, suggesting subclinical infection accompanied by prion shedding. 138N-PrP C was less efficiently converted to PrP res in vitro than wild-type deer (138SS) PrP C . Heterozygous coexpression of wild-type deer and 138N-PrP C resulted in dominant-negative inhibition and progressively diminished prion conversion over serial rounds of protein misfolding cyclic amplification. Our study indicates that heterozygosity at a polymorphic Prnp codon can confer the highest protection against clinical CWD and highlights the potential role of subclinical carriers in CWD transmission.

Funder

Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada

Canada Research Chairs

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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