A 7-kDa prion protein (PrP) fragment, an integral component of the PrP region required for infectivity, is the major amyloid protein in Gerstmann-Straussler-Scheinker disease A117V

Gerstmann-Straussler-Scheinker disease (GSS) is a cerebral amyloidosis asso ciated with mutations in the prion protein (PrP) gene (PRNP), The aim of th is study was to characterize amyloid peptides purified from brain tissue of a patient with the A117V mutation who was Met/Val heterozygous at codon 12 9, Val(129) being in coupling phase with mutant Val(117). The major peptide extracted from amyloid fibrils was a similar to7-kDa PrP fragment. Sequenc e analysis and mass spectrometry showed that this fragment had ragged N and C termini, starting mainly at Gly(88) and Gly(90) and ending with Arg(148) , Glu(152) or Asn(153). Only Val was present at positions 117 and 129, indi cating that the amyloid protein originated from mutant PrP molecules. In ad dition to the similar to7-kDa peptides, the amyloid fraction contained N- a nd C-terminal PrP fragments corresponding to residues 23-41, 191-205, and 2 17-228, Fibrillogenesis in vitro with synthetic peptides corresponding to P rP fragments extracted from brain tissue showed that peptide PrP-(85-148) r eadily assembled into amyloid fibrils, Peptide PrP-(191-205) also formed fi brillary structures although with different morphology, whereas peptides Pr P-(23-41) and PrP-(217-228) did not, These findings suggest that the proces sing of mutant PrP isoforms associated with Gerstmann-Straussler-Scheinker disease may occur extracellularly. It is conceivable that full-length PrP a nd/or large PrP peptides are deposited in the extracellular compartment, pa rtially degraded by proteases and further digested by tissue endopeptidases , originating a similar to7-kDa protease-resistant core that is similar in patients with different mutations, Furthermore, the present data suggest th at C-terminal fragments of PrP may participate in amyloid formation.