Prion proteins with different conformations accumulate in Geustmann-Straussler-Scheinker disease caused by A117V and F198S mutations

Gerstmann-Straussler-Scheinker disease (GSS) is characterized by the accumulation of proteinase K (PK)-resistant prion protein fragments (PrPSC) of similar to7 to 15 kd in the brain. Purified GSS amyloid is composed primarily of similar to7-kd PrP peptides, whose N terminus corresponds to residues W-81 and G(88) to G(90) in patients with the A117V mutation and to residue W-81 in patients with the F198S mutation, The aim of this study was to characterize PrP in brain extracts, microsomal preparations, and purified fractions from A117V patients and to determine the N terminus of PrPSC species in both GSS A117V and F198S. in all GSS A117V patients, the similar to7-kd PrPSC fragment isolated from nondigested and PK-digested samples had the major N terminus at residue G(88) and G(90), respectively, Conversely, in all patients with GSS F198S, an similar to8-kd prp(SC) fragment was isolated having the major N terminus start at residue G(74). If is possible that a further degradation of this fragment generates the amyloid subunit starting at W-81. The finding that patients with GSS A117V and F198S accumulate PrPSC fragments of different size and N-terminal sequence, suggests that these mutations generate two distinct PrP conformers.