Gerstmann-Sträussler-Scheinker disease (GSS) is a
prion-related
encephalopathy pathologically characterized by massive deposition of
prion protein (PrP)
amyloid in the central nervous system. The major component 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 approximately 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 consecutive 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 mutant).
Peptide PrP-(106-126) formed straight fibrils similar to those extracted 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 fibrils had tinctorial and conformational properties of native
amyloid. Conversely, the other
peptides did not form
amyloid-like fibrils under similar conditions. These findings suggest that the sequence spanning residues 106-147 of PrP is central to
amyloid fibril formation in GSS and related
encephalopathies.