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 accumu lation of proteinase K (PK)-resistant prion protein fragments (PrPSC) of si milar 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 chara cterize PrP in brain extracts, microsomal preparations, and purified fracti ons 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 Pr PSC fragment isolated from nondigested and PK-digested samples had the majo r N terminus at residue G(88) and G(90), respectively, Conversely, in all p atients with GSS F198S, an similar to8-kd prp(SC) fragment was isolated hav ing the major N terminus start at residue G(74). If is possible that a furt her degradation of this fragment generates the amyloid subunit starting at W-81. The finding that patients with GSS A117V and F198S accumulate PrPSC f ragments of different size and N-terminal sequence, suggests that these mut ations generate two distinct PrP conformers.