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

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DOI

https://doi.org/10.1073/pnas.2221060120

Language of the publication
English
Date
2023-04-04
Type
Article
Author(s)
  • Arifin, Maria I.
  • Kaczmarczyk, Lech
  • Zeng, Doris
  • Hannaoui, Samia
  • Lee, Chi
  • Chang, Sheng Chun
  • Mitchell, Gordon
  • McKenzie, Debbie
  • Beekes, Michael
  • Jackson, Walker
  • Gilch, Sabine
Publisher
National Academy of Sciences

Abstract

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.

Subject

  • Health and safety,
  • Science and technology

Keywords

  • Chronic wasting disease,
  • Maladie du dépérissement chronique,
  • Prion disease,
  • Transmissible spongiform encephalopathies,
  • TSE,
  • Prions

Rights

Pagination

1-10

Peer review

Yes

Open access level

Gold

Identifiers

ISSN
0027-8424
1091-6490

Article

Journal title
Proceedings of the National Academy of Sciences of the United States of America
Journal volume
120
Journal issue
15
Article number
e2221060120
Accepted date
2023-03-06
Submitted date
2022-12-12

Citation(s)

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 of the United States of America, 150(15), Article e2221060120. https://doi.org/10.1073/pnas.2221060120

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