Prion disease tempo determined by host-dependent substrate reduction

C.E. Mays, C. Kim, T. Haldiman, J. v.d. Merwe, A. Lau, J. Yang, J. Grams, M.A. Di Bari, R. Nonno, G.C. Telling, Q. Kong, J.P.M. Langeveld, D. McKenzie, D. Westaway, J.G. Safar

Research output: Contribution to journalArticleAcademicpeer-review

45 Citations (Scopus)

Abstract

The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the misfolded prion protein (PrPSc), which is derived from its cellular precursor (PrPC), as well as downregulation of the PrP-like Shadoo (Sho) glycoprotein. Given the overlapping cellular environments for PrPC and Sho, we inferred that PrPC levels might also be altered as part of a host response during prion infection. Using rodent models, we found that, in addition to changes in PrPC glycosylation and proteolytic processing, net reductions in PrPC occur in a wide range of prion diseases, including sheep scrapie, human Creutzfeldt-Jakob disease, and cervid chronic wasting disease. The reduction in PrPC results in decreased prion replication, as measured by the protein misfolding cyclic amplification technique for generating PrPSc in vitro. While PrPC downregulation is not discernible in animals with unusually short incubation periods and high PrPC expression, slowly evolving prion infections exhibit downregulation of the PrPC substrate required for new PrPSc synthesis and as a receptor for pathogenic signaling. Our data reveal PrPC downregulation as a previously unappreciated element of disease pathogenesis that defines the extensive, presymptomatic period for many prion strains
Original languageEnglish
Pages (from-to)847-858
JournalThe Journal of Clinical Investigation
Volume124
Issue number2
DOIs
Publication statusPublished - 2014

Keywords

  • chronic wasting disease
  • transgenic mice
  • cyclic amplification
  • cultured-cells
  • sheep scrapie
  • prpsc levels
  • protein
  • propagation
  • immunoassay
  • strains

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