title: Phenotypic variability of Gerstmann-Sträussler-Scheinker disease is associated with prion protein heterogeneity.
abstract: Gerstmann-Sträussler-Scheinker disease (GSS), a cerebello-pyramidal syndrome associated with dementia and caused by mutations in the prion protein gene (PRNP), is phenotypically heterogeneous. The molecular mechanisms responsible for such heterogeneity are unknown. Since we hypothesize that prion protein (PrP) heterogeneity may be associated with clinico-pathologic heterogeneity, the aim of this study was to analyze PrP in several GSS variants. Among the pathologic phenotypes of GSS, we recognize those without and with marked spongiform degeneration. In the latter (i.e. a subset of GSS P102L patients) we observed 3 major proteinase-K resistant PrP (PrPres) isoforms of ca. 21-30 kDa, similar to those seen in Creutzfeldt-Jakob disease. In contrast, the 21-30 kDa isoforms were not prominent in GSS variants without spongiform changes, including GSS A117V, GSS D202N, GSS Q212P, GSS Q217R, and 2 cases of GSS P102L. This suggests that spongiform changes in GSS are related to the presence of high levels of these distinct 21-30 kDa isoforms. Variable amounts of smaller, distinct PrPres isoforms of ca. 7-15 kDa were seen in all GSS variants. This suggests that GSS is characterized by the presence PrP isoforms that can be partially cleaved to low molecular weight PrPres peptides.
authors.affiliation: Indiana University School of Medicine, Indianapolis 46202-5120, USA.
authors.forename: P
authors.initials: P
authors.lastname: Piccardo
authors.forename: S R
authors.initials: SR
authors.lastname: Dlouhy
authors.forename: P M
authors.initials: PM
authors.lastname: Lievens
authors.forename: K
authors.initials: K
authors.lastname: Young
authors.forename: T D
authors.initials: TD
authors.lastname: Bird
authors.forename: D
authors.initials: D
authors.lastname: Nochlin
authors.forename: D W
authors.initials: DW
authors.lastname: Dickson
authors.forename: H V
authors.initials: HV
authors.lastname: Vinters
authors.forename: T R
authors.initials: TR
authors.lastname: Zimmerman
authors.forename: I R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: S J
authors.initials: SJ
authors.lastname: Kish
authors.forename: L C
authors.initials: LC
authors.lastname: Ang
authors.forename: C
authors.initials: C
authors.lastname: De Carli
authors.forename: M
authors.initials: M
authors.lastname: Pocchiari
authors.forename: P
authors.initials: P
authors.lastname: Brown
authors.forename: C J
authors.initials: CJ
authors.lastname: Gibbs
authors.forename: D C
authors.initials: DC
authors.lastname: Gajdusek
authors.forename: O
authors.initials: O
authors.lastname: Bugiani
authors.forename: J
authors.initials: J
authors.lastname: Ironside
authors.forename: F
authors.initials: F
authors.lastname: Tagliavini
authors.forename: B
authors.initials: B
authors.lastname: Ghetti
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D004247:DNA / Q000032:analysis / Q000235:genetics; D005260:Female; D016098:Gerstmann-Straussler-Scheinker Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D010641:Phenotype; D011328:Prions / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011328:Prions; D004247:DNA