SYNTHETIC PEPTIDES HOMOLOGOUS TO PRION PROTEIN RESIDUES 106-147 FORM AMYLOID-LIKE FIBRILS IN-VITRO

Gerstmann-Straussler-Scheinker disease (GSS) is a prion-related enceph alopathy pathologically characterized by massive deposition of prion p rotein (PrP) amyloid in the central nervous system. The major componen t of amyloid fibrils isolated from patients of the Indiana kindred of GSS (GSS-Ik) is an 11-kDa fragment of PrP spanning residues 58 to almo st-equal-to 150. These patients carry a missense mutation of the PRNP gene, causing a Phe --> Ser substitution at codon 198. We investigated fibrillogenesis in vitro by using synthetic peptides homologous to co nsecutive segments of GSS-Ik amyloid protein (residues 57-64, 89-106, 106-126, and 127-147) as well as peptides from the PrP region with the GSS-Ik mutation (residues 191-205 and 181-205, both wild type and mut ant). Peptide PrP-(106-126) formed straight fibrils similar to those e xtracted from GSS brains, whereas peptide PrP-(127-147) formed twisted fibrils resembling scrapie-associated fibrils isolated from subjects with transmissible spongiform encephalopathies. Congo red staining and x-ray fibril diffraction showed that both straight and twisted fibril s had tinctorial and conformational properties of native amyloid. Conv ersely, the other peptides did not form amyloid-like fibrils under sim ilar conditions. These findings suggest that the sequence spanning res idues 106-147 of PrP is central to amyloid fibril formation in GSS and related encephalopathies.