title: Prion propagation and toxicity in vivo occur in two distinct mechanistic phases.
abstract: Mammalian prions cause fatal neurodegenerative conditions including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. Prion infections are typically associated with remarkably prolonged but highly consistent incubation periods followed by a rapid clinical phase. The relationship between prion propagation, generation of neurotoxic species and clinical onset has remained obscure. Prion incubation periods in experimental animals are known to vary inversely with expression level of cellular prion protein. Here we demonstrate that prion propagation in brain proceeds via two distinct phases: a clinically silent exponential phase not rate-limited by prion protein concentration which rapidly reaches a maximal prion titre, followed by a distinct switch to a plateau phase. The latter determines time to clinical onset in a manner inversely proportional to prion protein concentration. These findings demonstrate an uncoupling of infectivity and toxicity. We suggest that prions themselves are not neurotoxic but catalyse the formation of such species from PrP(C). Production of neurotoxic species is triggered when prion propagation saturates, leading to a switch from autocatalytic production of infectivity (phase 1) to a toxic (phase 2) pathway.
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Malin K
authors.initials: MK
authors.lastname: Sandberg
authors.forename: Huda
authors.initials: H
authors.lastname: Al-Doujaily
authors.forename: Bernadette
authors.initials: B
authors.lastname: Sharps
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Clarke
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000818:Animals; D055162:Biocatalysis; D001681:Biological Assay; D004195:Disease Models, Animal; D015870:Gene Expression; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018621:PrPC Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018620:PrPSc Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000472:pathogenicity* / Q000633:toxicity; D017096:Prion Diseases / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology / Q000635:transmission; D015996:Survival Rate; D013997:Time Factors; D018675:Toxicity Tests
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins