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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 53

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 8

Summary of PrPC and Sho downregulation in a prion-infected cell by an unidentified degradation pathway.

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Summary of PrPC and Sho downregulation in a prion-infected cell by an un...
(A) In a healthy cell, the balance of synthesis rate and degradation rate establish the steady-state level of PrPC and Sho. (B) We assert that prion-infected cells are characterized by two processes. The first is the well-known biosynthetic conversion of PrPC to PrPSc (top part of cell). We hypothesize a second process (bottom part of the cell) in which the accumulation of PrPSc triggers (open arrow) a proteostatic degradative response (Pac-Man shape). This in turn reduces the steady-state concentrations of PrPC and Sho (indicated by smaller text) by a “bystander effect”. Reduced PrPC will have an impact on PrPSc synthesis (dotted green line). An additional effect of PrPC reduction may be to attenuate toxic signaling (see the Discussion), but this concept is omitted from the diagram for the sake of simplicity.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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