title: Co-existence of distinct prion types enables conformational evolution of human PrPSc by competitive selection.
abstract: The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrP(Sc)). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrP(Sc) particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease. The protein misfolding cyclic amplification replicates each of the PrP(Sc) particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrP(C) substrate, the dominant PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sporadic Creutzfeldt-Jakob disease PrP(Sc) is not a single conformational entity but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers.
authors: From the Departments of Pathology and.
authors: Tracy
authors: T
authors: Haldiman
authors: Chae
authors: C
authors: Kim
authors: Yvonne
authors: Y
authors: Cohen
authors: Wei
authors: W
authors: Chen
authors: Janis
authors: J
authors: Blevins
authors: Liuting
authors: L
authors: Qing
authors: Mark L
authors: ML
authors: Cohen
authors: Jan
authors: J
authors: Langeveld
authors: Glenn C
authors: GC
authors: Telling
authors: Qingzhong
authors: Q
authors: Kong
authors: Jiri G
authors: JG
authors: Safar
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D007118:Immunoassay; D009154:Mutation; D018620:PrPSc Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011328:Prions / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D055550:Protein Stability; D012641:Selection, Genetic
chemical_list: D018620:PrPSc Proteins; D011328:Prions
keywords: Molecular Evolution; Neurobiology; Neurodegeneration; Prions; Protein Conformation; Sporadic Creutzfeldt-Jakob Disease
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