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Citations to this article

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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Total citations by year

Year: 2025 2024 2022 2021 2020 2019 2018 2017 2016 2015 2014 Total
Citations: 3 4 8 2 6 6 4 6 3 7 1 50
Citation information
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Citations to this article in year 2020 (6)

Title and authors Publication Year
Chronic wasting disease (CWD) prion strains evolve via adaptive diversification of conformers in hosts expressing prion protein polymorphisms
CD Velásquez, C Kim, T Haldiman, C Kim, A Herbst, J Aiken, JG Safar, D McKenzie
The Journal of biological chemistry 2020
Prion protein PrP nucleic acid binding and mobilization implicates retroelements as the replicative component of transmissible spongiform encephalopathy
R Lathe, JL Darlix
Archives of Virology 2020
Diverse, evolving conformer populations drive distinct phenotypes in frontotemporal lobar degeneration caused by the same MAPT-P301L mutation
N Daude, C Kim, SG Kang, G Eskandari-Sedighi, T Haldiman, J Yang, SC Fleck, E Gomez-Cardona, ZZ Han, S Borrego-Ecija, S Wohlgemuth, O Julien, H Wille, L Molina-Porcel, E Gelpi, JG Safar, D Westaway
Acta Neuropathologica 2020
Host prion protein expression levels impact prion tropism for the spleen
V Béringue, P Tixador, O Andréoletti, F Reine, J Castille, TL Laï, AL Dur, A Laisné, L Herzog, B Passet, H Rezaei, JL Vilotte, H Laude, NA Mabbott
PLoS pathogens 2020
Quaternary Structure Changes for PrPSc Predate PrPC Downregulation and Neuronal Death During Progression of Experimental Scrapie Disease
G Eskandari-Sedighi, LM Cortez, J Yang, N Daude, K Shmeit, V Sim, D Westaway
Molecular Neurobiology 2020
Incomplete glycosylation during prion infection unmasks a prion protein epitope that facilitates prion detection and strain discrimination
HE Kang, J Bian, SJ Kane, S Kim, V Selwyn, J Crowell, JC Bartz, GC Telling
The Journal of biological chemistry 2020

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