title: Small ruminant nor98 prions share biochemical features with human gerstmann-sträussler-scheinker disease and variably protease-sensitive prionopathy.
abstract: Prion diseases are classically characterized by the accumulation of pathological prion protein (PrP(Sc)) with the protease resistant C-terminal fragment (PrP(res)) of 27-30 kDa. However, in both humans and animals, prion diseases with atypical biochemical features, characterized by PK-resistant PrP internal fragments (PrP(res)) cleaved at both the N and C termini, have been described. In this study we performed a detailed comparison of the biochemical features of PrP(Sc) from atypical prion diseases including human Gerstmann-Sträussler-Scheinker disease (GSS) and variably protease-sensitive prionopathy (VPSPr) and in small ruminant Nor98 or atypical scrapie. The kinetics of PrP(res) production and its cleavage sites after PK digestion were analyzed, along with the PrP(Sc) conformational stability, using a new method able to characterize both protease-resistant and protease-sensitive PrP(Sc) components. All these PrP(Sc) types shared common and distinctive biochemical features compared to PrP(Sc) from classical prion diseases such as sporadic Creutzfeldt-Jakob disease and scrapie. Notwithstanding, distinct biochemical signatures based on PrP(res) cleavage sites and PrP(Sc) conformational stability were identified in GSS A117V, GSS F198S, GSS P102L and VPSPr, which allowed their specific identification. Importantly, the biochemical properties of PrP(Sc) from Nor98 and GSS P102L largely overlapped, but were distinct from the other human prions investigated. Finally, our study paves the way towards more refined comparative approaches to the characterization of prions at the animal-human interface.
authors.affiliation: Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy. laura.pirisinu@iss.it
authors.forename: Laura
authors.initials: L
authors.lastname: Pirisinu
authors.forename: Romolo
authors.initials: R
authors.lastname: Nonno
authors.forename: Elena
authors.initials: E
authors.lastname: Esposito
authors.forename: Sylvie L
authors.initials: SL
authors.lastname: Benestad
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.forename: Umberto
authors.initials: U
authors.lastname: Agrimi
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Zou
mesh_terms: D000818:Animals; D018604:Epitope Mapping; D016098:Gerstmann-Straussler-Scheinker Disease / Q000378:metabolism*; D006801:Humans; D010447:Peptide Hydrolases / Q000378:metabolism; D018620:PrPSc Proteins / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism*; D012418:Ruminants
chemical_list: D018620:PrPSc Proteins; D010447:Peptide Hydrolases