title: Prion proteins with different conformations accumulate in Gerstmann-Sträussler-Scheinker disease caused by A117V and F198S mutations.
abstract: Gerstmann-Sträussler-Scheinker disease (GSS) is characterized by the accumulation of proteinase K (PK)-resistant prion protein fragments (PrP(sc)) of approximately 7 to 15 kd in the brain. Purified GSS amyloid is composed primarily of approximately 7-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 PrP(sc) species in both GSS A117V and F198S. In all GSS A117V patients, the approximately 7-kd PrP(sc) 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 approximately 8-kd PrP(sc) fragment was isolated having the major N terminus start at residue G(74). It 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 PrP(sc) fragments of different size and N-terminal sequence, suggests that these mutations generate two distinct PrP conformers.
authors.affiliation: Indiana Alzheimer Disease Center and the Departments of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202-5120, USA. ppiccard@iupui.edu
authors.forename: P
authors.initials: P
authors.lastname: Piccardo
authors.forename: J J
authors.initials: JJ
authors.lastname: Liepnieks
authors.forename: A
authors.initials: A
authors.lastname: William
authors.forename: S R
authors.initials: SR
authors.lastname: Dlouhy
authors.forename: M R
authors.initials: MR
authors.lastname: Farlow
authors.forename: K
authors.initials: K
authors.lastname: Young
authors.forename: D
authors.initials: D
authors.lastname: Nochlin
authors.forename: T D
authors.initials: TD
authors.lastname: Bird
authors.forename: R R
authors.initials: RR
authors.lastname: Nixon
authors.forename: M J
authors.initials: MJ
authors.lastname: Ball
authors.forename: C
authors.initials: C
authors.lastname: DeCarli
authors.forename: O
authors.initials: O
authors.lastname: Bugiani
authors.forename: F
authors.initials: F
authors.lastname: Tagliavini
authors.forename: M D
authors.initials: MD
authors.lastname: Benson
authors.forename: B
authors.initials: B
authors.lastname: Ghetti
mesh_terms: D000682:Amyloid / Q000235:genetics*; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002457:Cell Extracts / Q000032:analysis; D019286:Endopeptidase K / Q000737:chemistry; D016098:Gerstmann-Straussler-Scheinker Disease / Q000235:genetics* / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry; D017354:Point Mutation; D018620:PrPSc Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D000072002:Prion Proteins; D011328:Prions; D011487:Protein Conformation; D011498:Protein Precursors / Q000235:genetics*; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D000682:Amyloid; D002457:Cell Extracts; C512656:PRNP protein, human; D010446:Peptide Fragments; D018620:PrPSc Proteins; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors; D019286:Endopeptidase K