Epitope scanning indicates structural differences in brain-derived monomeric and aggregated mutant prion proteins related to genetic prion diseases

Laura Tapella, Matteo Stravalaci, Antonio Bastone, Emiliano Biasini, Marco Gobbi, Roberto Chiesa

Research output: Contribution to journalArticle

Abstract

Genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia and prion protein cerebral amyloid angiopathy are clinically and neuropathologically distinct neurodegenerative diseases linked to mutations in the PRNP gene encoding the cellular prion protein (PrPC). How sequence variants of PRNP encode the information to specify these disease phenotypes is not known. It is suggested that each mutation produces a misfolded variant of PrPC with specific neurotoxic properties. However, structural studies of recombinant PrP did not detect major differences between wild-type andmutant molecules, pointing to the importance of investigatingmutant PrPs from mammalian brains. We used surface plasmon resonance and a slot-blot immunoassay to analyse the antibody-binding profiles of soluble and insoluble PrP molecules extracted from the brains of transgenic mice modelling different prion diseases. By measuring the reactivity of monoclonal antibodies against different PrP epitopes, we obtained evidence of conformational differences between wild-type and mutant PrPs, and among different mutants. We detected structural heterogeneity in both monomeric and aggregated PrP, supporting the hypothesis that the phenotype of genetic prion diseases is encoded by mutant PrP conformation and assembly state.

Original languageEnglish
Pages (from-to)417-425
Number of pages9
JournalBiochemical Journal
Volume454
Issue number3
DOIs
Publication statusPublished - Sep 15 2013

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Keywords

  • Genetic prion disease
  • Prion protein (PrP)
  • Protein aggregation
  • Protein misfolding

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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