title: Synthetic scrapie infectivity: interaction between recombinant PrP and scrapie brain-derived RNA.
abstract: The key molecular event in human cerebral proteinopathies, which include Alzheimer's, Parkinson's and Huntington's diseases, is the structural conversion of a specific host protein into a β-sheet-rich conformer. With regards to this common mechanism, it appears difficult to explain the outstanding infectious properties attributed to PrP(Sc), the hallmark of another intriguing family of cerebral proteinopathies known as transmissible spongiform encephalopathies (TSE) or prion diseases. The infectious PrP(Sc) or "prion" is thought to be composed solely of a misfolded form of the otherwise harmless cellular prion protein (PrP(c)). To gain insight into this unique situation, we used the 263K scrapie hamster model to search for a putative PrP(Sc)-associated factor that contributes to the infectivity of PrP(Sc) amyloid. In a rigorously controlled set of experiments that included several bioassays, we showed that originally innocuous recombinant prion protein (recPrP) equivalent to PrP(c) is capable of initiating prion disease in hamsters when it is converted to a prion-like conformation (β-sheet-rich) in the presence of RNA purified from scrapie-associated fibril (SAF) preparations. Analysis of the recPrP-RNA infectious mixture reveals the presence of 2 populations of small RNAs of approximately 27 and 55 nucleotides. These unprecedented findings are discussed in light of the distinct relationship that may exist between this RNA material and the 2 biological properties, infectivity and strain features, attributed to prion amyloid.
authors.affiliation: a Division of Prions and Related Diseases (SEPIA); Institute of Emerging Diseases and Innovative Therapies (iMETI); CEA ; Fontenay-aux-Roses, France.
authors.forename: Steve
authors.initials: S
authors.lastname: Simoneau
authors.forename: Achim
authors.initials: A
authors.lastname: Thomzig
authors.forename: Marie-Madeleine
authors.initials: MM
authors.lastname: Ruchoux
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vignier
authors.forename: Martin L
authors.initials: ML
authors.lastname: Daus
authors.forename: Anna
authors.initials: A
authors.lastname: Poleggi
authors.forename: Pierre
authors.initials: P
authors.lastname: Lebon
authors.forename: Sophie
authors.initials: S
authors.lastname: Freire
authors.forename: Valerie
authors.initials: V
authors.lastname: Durand
authors.forename: Silvia
authors.initials: S
authors.lastname: Graziano
authors.forename: Roberta
authors.initials: R
authors.lastname: Galeno
authors.forename: Franco
authors.initials: F
authors.lastname: Cardone
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Comoy
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pocchiari
authors.forename: Michael
authors.initials: M
authors.lastname: Beekes
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Deslys
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: Fournier
mesh_terms: D000682:Amyloid / Q000032:analysis*; D000818:Animals; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D001923:Brain Chemistry; D006224:Cricetinae; D008854:Microscopy, Electron; D018620:PrPSc Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000472:pathogenicity*; D017433:Protein Structure, Secondary; D012313:RNA / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012608:Scrapie / Q000209:etiology*
chemical_list: D000682:Amyloid; D018620:PrPSc Proteins; D011994:Recombinant Proteins; D012313:RNA
keywords: PMCA; PrPsc; RNA; SAF-derived RNA; nature of prions; prion infectivity; prions; recombinant PrP; scrapie infectivity