A 7-kDa Prion Protein (PrP) Fragment, an Integral Component of the PrP Region Required for Infectivity, Is the Major Amyloid Protein in Gerstmann-Sträussler-Scheinker Disease A117V

Fabrizio Tagliavini, Patricia M.J. Lievens, Christine Tranchant, Jean Marie Warter, Michel Mohr, Giorgio Giaccone, Francesco Perini, Giacomina Rossi, Mario Salmona, Pedro Piccardo, Bernardino Ghetti, Ronald C. Beavis, Orso Bugiani, Blas Frangione, Frances Prelli

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107 Scopus citations

Abstract

Gerstmann-Str̈ussler-Scheinker disease (GSS) is a cerebral amyloidosis associated with mutations in the prion protein (PrP) gene (PRNP). The aim of this study was to characterize amyloid peptides purified from brain tissue of a patient with the A117V mutation who was Met/Val heterozygous at codon 129, Val129 being in coupling phase with mutant Val117. The major peptide extracted from amyloid fibrils was a ∼7-kDa PrP fragment. Sequence analysis and mass spectrometry showed that this fragment had ragged N and C termini, starting mainly at Gly88 and Gly90 and ending with Arg148 Glu152, or Asn153. Only Val was present at positions 117 and 129, indicating that the amyloid protein originated from mutant PrP molecules. In addition to the ∼7-kDa peptides, the amyloid fraction contained N- and C-terminal PrP fragments corresponding to residues 23-41, 191-205, and 217-228. Fibrillogenesis in vitro with synthetic peptides corresponding to PrP fragments extracted from brain tissue showed that peptide PrP-(85-148) readily assembled into amyloid fibrils. Peptide PrP-(191-205) also formed fibrillary structures although with different morphology, whereas peptides PrP-(23-41) and PrP-(217-228) did not. These findings suggest that the processing of mutant PrP isoforms associated with Gerstmann-Sträussler-Scheinker disease may occur extracellularly. It is conceivable that full-length PrP and/or large PrP peptides are deposited in the extracellular compartment, partially degraded by proteases and further digested by tissue endopeptidases, originating a ∼7-kDa protease-resistant core that is similar in patients with different mutations. Furthermore, the present data suggest that C-terminal fragments of PrP may participate in amyloid formation.

Original languageEnglish (US)
Pages (from-to)6009-6015
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number8
DOIs
StatePublished - Feb 23 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Tagliavini, F., Lievens, P. M. J., Tranchant, C., Warter, J. M., Mohr, M., Giaccone, G., Perini, F., Rossi, G., Salmona, M., Piccardo, P., Ghetti, B., Beavis, R. C., Bugiani, O., Frangione, B., & Prelli, F. (2001). A 7-kDa Prion Protein (PrP) Fragment, an Integral Component of the PrP Region Required for Infectivity, Is the Major Amyloid Protein in Gerstmann-Sträussler-Scheinker Disease A117V. Journal of Biological Chemistry, 276(8), 6009-6015. https://doi.org/10.1074/jbc.M007062200