allelic origin of protease-sensitive and protease-resistant prion protein isoforms in gerstmann-str？ussler-scheinker disease with the p102l mutation等位基因的起源protease-sensitive和protease-resistant朊蛋白亚型gerstmann-str ussler-scheinker p102l突变的疾病.pdfVIP

Allelic Origin of Protease-Sensitive and Protease- Resistant Prion Protein Isoforms in Gerstmann- ¨ Straussler-Scheinker Disease with the P102L Mutation 1 1 1 1 1 Salvatore Monaco *, Michele Fiorini , Alessia Farinazzo , Sergio Ferrari , Matteo Gelati , Pedro 2,3 1 3 Piccardo , Gianluigi Zanusso , Bernardino Ghetti 1 Department of Neurological, Neuropsychological, Morphological and Motor Sciences, University of Verona, Verona, Italy, 2 Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland, United States of America, 3 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America Abstract ¨ Gerstmann-Straussler-Scheinker (GSS) disease is a dominantly inherited prion disease associated with point mutations in the Prion Protein gene. The most frequent mutation associated with GSS involves a proline-to-leucine substitution at residue 102 of the prion protein, and is characterized by marked variability at clinical, pathological and molecular levels. Previous investigations of GSS P102L have shown that disease-associated pathological prion protein, or PrPSc, consists of two main conformers, which under exogenous proteolysis generates a core fragment of 21 kDa and an internal fragment of 8 kDa. Both conformers are detected in subjects with spongiform degeneration, whereas only the 8 kDa fragment is recovered in cases lacking spongiosis. Several studies have reported an exclusive derivation of protease-resistant PrPSc isoforms from the mutated allele; however, more recently, the propagation of protease-resistant wild-type PrPSc has been descri