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.
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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Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation
A Lau, A McDonald, N Daude, CE Mays, ED Walter, R Aglietti, RC Mercer, S Wohlgemuth, J der Merwe, J Yang, H Gapeshina, C Kim, J Grams, B Shi, H Wille, A Balachandran, G Schmitt-Ulms, JG Safar, GL Millhauser, D Westaway |
EMBO Molecular Medicine | 2015 |
Rapidly progressive Alzheimer's disease features distinct structures of amyloid-
ML Cohen, C Kim, T Haldiman, M ElHag, P Mehndiratta, T Pichet, F Lissemore, M Shea, Y Cohen, W Chen, J Blevins, BS Appleby, K Surewicz, WK Surewicz, M Sajatovic, C Tatsuoka, S Zhang, P Mayo, M Butkiewicz, JL Haines, AJ Lerner, JG Safar |
Brain | 2015 |
Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation
A Alleaume-Butaux, S Nicot, M Pietri, A Baudry, C Dakowski, P Tixador, H Ardila-Osorio, AM Haeberlé, Y Bailly, JM Peyrin, JM Launay, O Kellermann, B Schneider, P Lingor |
PLoS pathogens | 2015 |
Early Generation of New PrPSc on Blood Vessels after Brain Microinjection of Scrapie in Mice
B Chesebro, J Striebel, A Rangel, K Phillips, A Hughson, B Caughey, B Race |
mBio | 2015 |
Prion Infectivity Plateaus and Conversion to Symptomatic Disease Originate from Falling Precursor Levels and Increased Levels of Oligomeric PrP Sc Species
CE Mays, J der Merwe, C Kim, T Haldiman, D McKenzie, JG Safar, D Westaway, BW Caughey |
Journal of virology | 2015 |
The prion protein constitutively controls neuronal store-operated Ca2+ entry through Fyn kinase
AD Mario, A Castellani, C Peggion, ML Massimino, D Lim, AF Hill, MC Sorgato, A Bertoli |
Frontiers in cellular neuroscience | 2015 |
Neuroprotective properties of the PrP-like Shadoo glycoprotein assessed in the middle cerebral artery occlusion model of ischemia
N Daude, H Gapeshina, B Dong, I Winship, D Westaway |
Prion | 2015 |