title: 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.forename: Charles E
authors.initials: CE
authors.lastname: Mays
authors.forename: Chae
authors.initials: C
authors.lastname: Kim
authors.forename: Tracy
authors.initials: T
authors.lastname: Haldiman
authors.forename: Jacques
authors.initials: J
authors.lastname: van der Merwe
authors.forename: Agnes
authors.initials: A
authors.lastname: Lau
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Grams
authors.forename: Michele A
authors.initials: MA
authors.lastname: Di Bari
authors.forename: Romolo
authors.initials: R
authors.lastname: Nonno
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Telling
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Kong
authors.forename: Jan
authors.initials: J
authors.lastname: Langeveld
authors.forename: Debbie
authors.initials: D
authors.lastname: McKenzie
authors.forename: David
authors.initials: D
authors.lastname: Westaway
authors.forename: Jiri G
authors.initials: JG
authors.lastname: Safar
mesh_terms: D000818:Animals; D003411:Arvicolinae; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism / Q000503:physiopathology; D018450:Disease Progression; D015536:Down-Regulation; D006031:Glycosylation; D006801:Humans; D008647:Mesocricetus; D051379:Mice; D008822:Mice, Transgenic; D018621:PrPC Proteins / Q000737:chemistry; D018620:PrPSc Proteins / Q000737:chemistry; D017096:Prion Diseases / Q000378:metabolism / Q000503:physiopathology*; D020033:Protein Isoforms / Q000737:chemistry; D012608:Scrapie / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction; D013997:Time Factors; D034081:Wasting Disease, Chronic
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins; D020033:Protein Isoforms