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

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creativework.keywords - en
Prion disease
Transmissible spongiform encephalopathies
creativework.keywords - fr
Maladies à prions
Encéphalopathies spongiformes transmissibles
dc.contributor.author
Arifin, Maria I.
Kaczmarczyk, Lech
Zeng, Doris
Hannaoui, Samia
Lee, Chi
Chang, Sheng Chun
Mitchell, Gordon
McKenzie, Debbie
Beekes, Michael
Jackson, Walker
Gilch, Sabine
dc.date.accepted
2023-03-06
dc.date.accessioned
2025-04-14T20:58:56Z
dc.date.available
2025-04-14T20:58:56Z
dc.date.issued
2023-04-04
dc.date.submitted
2022-12-12
dc.description.abstract - en
Prions are proteinaceous infectious particles that replicate by structural conversion of the host-encoded cellular prion protein (PrPC), 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 PrPC 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 (PrPres) 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-PrPC was less efficiently converted to PrPres in vitro than wild-type deer (138SS) PrPC. Heterozygous coexpression of wild-type deer and 138N-PrPC 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.
dc.identifier.citation
Arifin, M. I., Kaczmarczyk, L., Zeng, D., Hannaoui, S., Lee, C., Chang, S. C., Mitchell, G., McKenzie, D., Beekes, M., Jackson, W., & Gilch, S. (2023). Heterozygosity for Cervid S138N polymorphism results in subclinical CWD in gene-targeted mice and progressive inhibition of prion conversion. Proceedings of the National Academy of Sciences, 120(15). https://doi.org/10.1073/pnas.2221060120
dc.identifier.doi
https://doi.org/10.1073/pnas.2221060120
dc.identifier.issn
1091-6490
dc.identifier.uri
https://open-science.canada.ca/handle/123456789/3602
dc.language.iso
en
dc.publisher - en
National Academy of Sciences
dc.rights - en
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
dc.rights - fr
Creative Commons Attribution - Pas d'utilisation commerciale - Pas de modification 4.0 International (CC BY-NC-ND 4.0)
dc.rights.uri - en
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.uri - fr
https://creativecommons.org/licenses/by-nc-nd/4.0/deed.fr
dc.subject - en
Animal diseases
Diseases
dc.subject - fr
Maladie animale
Maladie
dc.subject.en - en
Animal diseases
Diseases
dc.subject.fr - fr
Maladie animale
Maladie
dc.title - en
Heterozygosity for cervid S138N polymorphism results in subclinical CWD in gene-targeted mice and progressive inhibition of prion conversion
dc.type - en
Article
dc.type - fr
Article
local.acceptedmanuscript.articlenum
e2221060120
local.article.journalissue
15
local.article.journaltitle - en
Proceedings of the National Academy of Sciences
local.article.journalvolume
120
local.peerreview - en
Yes
local.peerreview - fr
Oui
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