title: Small protease sensitive oligomers of PrPSc in distinct human prions determine conversion rate of PrP(C).
abstract: The mammalian prions replicate by converting cellular prion protein (PrP(C)) into pathogenic conformational isoform (PrP(Sc)). Variations in prions, which cause different disease phenotypes, are referred to as strains. The mechanism of high-fidelity replication of prion strains in the absence of nucleic acid remains unsolved. We investigated the impact of different conformational characteristics of PrP(Sc) on conversion of PrP(C) in vitro using PrP(Sc) seeds from the most frequent human prion disease worldwide, the Creutzfeldt-Jakob disease (sCJD). The conversion potency of a broad spectrum of distinct sCJD prions was governed by the level, conformation, and stability of small oligomers of the protease-sensitive (s) PrP(Sc). The smallest most potent prions present in sCJD brains were composed only of∼20 monomers of PrP(Sc). The tight correlation between conversion potency of small oligomers of human sPrP(Sc) observed in vitro and duration of the disease suggests that sPrP(Sc) conformers are an important determinant of prion strain characteristics that control the progression rate of the disease.
authors.affiliation: National Prion Disease Surveillance Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Chae
authors.initials: C
authors.lastname: Kim
authors.forename: Tracy
authors.initials: T
authors.lastname: Haldiman
authors.forename: Krystyna
authors.initials: K
authors.lastname: Surewicz
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Cohen
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Janis
authors.initials: J
authors.lastname: Blevins
authors.forename: Man-Sun
authors.initials: MS
authors.lastname: Sy
authors.forename: Mark
authors.initials: M
authors.lastname: Cohen
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Kong
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Telling
authors.forename: Witold K
authors.initials: WK
authors.lastname: Surewicz
authors.forename: Jiri G
authors.initials: JG
authors.lastname: Safar
mesh_terms: D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary
chemical_list: D018620:PrPSc Proteins