Proteinase-K-Resistant Prion Protein Isoforms in Gerstmann-Straussler-Scheinker Disease (Indiana Kindred)

• Published in: Journal of neuropathology and experimental neurology 1996-11, Vol.55 (11), p.1157-1163
• Main Authors: Piccardo, Pedro, Seiler, Charles, Dlouhy, Stephen R, Young, Katherine, Farlow, Martin R, Prelli, Frances, Frangione, Blas, Bugiani, Orso, Tagliavini, Fabrizio, Ghetti, Bernardino
• Format: Article
• Language: English
• Subjects: Adult; Aged; Amyloid - metabolism; Amyloidosis; Analysis; Biological and medical sciences; Brain - metabolism; Brain - pathology; Care and treatment; Creutzfeldt-Jakob Syndrome - metabolism; Creutzfeldt-Jakob Syndrome - pathology; Drug Resistance; Endopeptidase K - pharmacology; Genetic aspects; Gerstmann-Straussler-Scheinker Disease - genetics; Gerstmann-Straussler-Scheinker Disease - metabolism; Gerstmann-Straussler-Scheinker Disease - pathology; Humans; Immunoblotting; Isomerism; Medical sciences; Middle Aged; Nervous system involvement in other diseases. Miscellaneous; Neurology; Prions (Proteins); Prions - drug effects; Prions - metabolism; Subcellular Fractions - metabolism
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/00005072-199611000-00007

Gerstmann-Straussler-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.