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Prion disease tempo determined by host-dependent substrate reduction
Charles E. Mays, … , David Westaway, Jiri G. Safar
Charles E. Mays, … , David Westaway, Jiri G. Safar
Published January 16, 2014
Citation Information: J Clin Invest. 2014;124(2):847-858. https://doi.org/10.1172/JCI72241.
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Research Article Neuroscience Article has an altmetric score of 57

Prion disease tempo determined by host-dependent substrate reduction

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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.

Authors

Charles E. Mays, Chae Kim, Tracy Haldiman, Jacques van der Merwe, Agnes Lau, Jing Yang, Jennifer Grams, Michele A. Di Bari, Romolo Nonno, Glenn C. Telling, Qingzhong Kong, Jan Langeveld, Debbie McKenzie, David Westaway, Jiri G. Safar

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Figure 6

Relationships between end point PrPC/PrPSc ratios and prion incubation period.

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Relationships between end point PrPC/PrPSc ratios and prion incubation p...
(A) Residual PrPC plotted against incubation time for the RML prion isolate in 3 mouse genotypes expressing different amounts of the PrP-A protein. Data points for mock-inoculated controls (yellow line) and end-stage RML prion-infected animals (green line) represent, from left to right, TgPrnpa-AL, WT FVB, and TgPrnpa mice all infected with the RML prion isolate. (B) Ratios of residual PrPC/residual PrPSc at disease end point plotted against incubation time for mouse genotypes presented in A. (C) Cumulative data for residual PrPC/residual PrPSc at disease end point for 8 prion strain/host genotype combinations.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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