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.

Gerstmann-Stra ̈ ussler-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 frag- ment. 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 mu- tant 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 pep- tides 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-Stra ̈ussler-Scheinker disease may occur ex- tracellularly. It is conceivable that full-length PrP and/or large PrP peptides are deposited in the extracel- lular compartment, partially degraded by proteases and further digested by tissue endopeptidases, originating a 7-kDa protease-resistant core that is similar in pa- tients with different mutations. Furthermore, the pres- ent data suggest that C-terminal fragments of PrP may participate in amyloid formation.