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

Prion disease tempo determined by host-dependent substrate reduction

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 3

Glycosylation and fragmentation of PrPC altered by prion infection.

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Glycosylation and fragmentation of PrPC altered by prion infection. (A...
(A) PrPC glycoform ratios for protein in gradient fractions 10, 9, and 8 for WT mouse brain and brains of mice with end-stage disease caused by RML, 22L, or 139A scrapie prions were determined for Western blots represented in Figure 1A and Supplemental Figure 1A. Diglycosylated, monoglycosylated, and unglycosylated forms are shown by circles, squares, and diamonds, respectively. The columns and error bars represent average ± SEM measured in 3 brains, each sample tested in duplicate or triplicate by CDI. The same gradient fractions for the 3 mouse-adapted scrapie samples were normalized by immunoblot signal and compared to uninfected controls (“healthy”) in blot analyses (B) before and (C) after PNGaseF deglycosylation. (D) Densitometry was performed to evaluate the net levels of full-length PrP and its C-terminal fragments (PrP C1 and PrP C2), as shown in C.