title: Proteinase-K-resistant prion protein isoforms in Gerstmann-Sträussler-Scheinker disease (Indiana kindred).
abstract: Gerstmann-Sträussler-Scheinker (GSS) disease is a cerebral prion protein (PrP) amyloidosis associated with mutations in the PrP gene (PRNP). A GSS disease variant with mutation at codon 198 (F198S) has been studied in a large Indiana kindred. Biochemical investigations showed that the amyloid protein consists of 11 and 7 kDa fragments of PrP. Immunohistochemical studies showed that in addition to amyloid, these patients accumulate PrP deposits which are neither fluorescent nor birefringent when stained with thioflavin S and Congo red. In the present paper, we analyzed proteinase-K (PK)-resistant PrP in 7 patients with GSS F198S disease. Immunoblots of PK-treated brain extracts show prominent bands of ca. 27-29, 18-19, and 8 kDa. Immunohistochemistry and thioflavin-S-fluorescence show that the amyloid deposits are conspicuous in the cerebellum but sparse in the caudate nucleus. However, immunoblot analysis reveals PK-resistant PrP bands of similar intensity in both regions. Treatment with PK and PNGase F generates a pattern similar to that of PK alone. Our findings suggest that brain extracts from GSS F198S disease contain 3 prominent nonglycosylated PK-resistant PrP fragments forming a pattern not previously described in other prion diseases, which may in part explain the pathology of this GSS disease variant.
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis 46202-5120, USA.
authors.forename: P
authors.initials: P
authors.lastname: Piccardo
authors.forename: C
authors.initials: C
authors.lastname: Seiler
authors.forename: S R
authors.initials: SR
authors.lastname: Dlouhy
authors.forename: K
authors.initials: K
authors.lastname: Young
authors.forename: M R
authors.initials: MR
authors.lastname: Farlow
authors.forename: F
authors.initials: F
authors.lastname: Prelli
authors.forename: B
authors.initials: B
authors.lastname: Frangione
authors.forename: O
authors.initials: O
authors.lastname: Bugiani
authors.forename: F
authors.initials: F
authors.lastname: Tagliavini
authors.forename: B
authors.initials: B
authors.lastname: Ghetti
mesh_terms: D000328:Adult; D000368:Aged; D000682:Amyloid / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism / Q000473:pathology; D004351:Drug Resistance; D019286:Endopeptidase K / Q000494:pharmacology*; D016098:Gerstmann-Straussler-Scheinker Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007536:Isomerism; D008875:Middle Aged; D011328:Prions / Q000187:drug effects* / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D000682:Amyloid; D011328:Prions; D019286:Endopeptidase K