NR AQRV
AU Piccardo,P.; Seiler,C.; Dlouhy,S.; Young,K.; Farlow,M.; Prelli,F.; Frangione,B.; Bugiani,O.; Tagliavini,F.; Ghetti,B.
TI Proteinase-K (PK) resistant prion protein (PrP) isoforms in Gerstmann-Sträussler-Scheinker disease (GSS) F198S
QU Journal of Neuropathology and Experimental Neurology 1996; 55(5): 636 Nr. 125
PT Meeting Abstract
VT
PROTEINASE K (PK) RESISTANT PRION PROTEIN (PRP) ISOFORMS IN GERSTMANN-STRÄUSSLER-SCHEINKER DISEASE (GSS) F198S.
P. Piccardo*1, C. Seiler1, S. Dlouhy, K. Young1, M. Farlow1, F. Prelli2, B. Frangione*2, O. Bugiani*3, F. Tagliavini*3, B. Ghetti*1
1 Indiana University School of Medicine, Indianapolis, IN; 2 New York University Medical Center, New York, NY; 3 Instituto Carlo Besta, Milano, Italy.
GSS, a cerebral amyloidosis with accumulation of fibrillar and nonfibrillar PrP, is caused by mutations in the PrP gene. The mechanism whereby mutation leads to disease is unknown. In GSS F198S, the major components of the amyloid fraction were shown to be 11 and 7 kDa peptides spanning PrP residues 58-150 and 81-150 respectively. Since PrP residue 197 is a potential site for glycosylation, we hypothesize that the F198S mutation affects PrP conformation and/or glycosylation, which in turn affects PrP processing and the formation of PK-resistant PrP (PrPRes). We analyzed PrPRes in the brains of seven patients with GSS F198S who had clinical signs for two to twelve years. Immunoblots of brain extracts probed with antibody 3F4, recognizing an epitope including PrP residues 109-112, show prominent PrPRes bands of ca. 27-29, 18-19 and 8 kDa. Immunohistochemistry and thioflavin S fluorescence show that amyloid is conspicuous in the cerebellum but sparse in the caudate nucleus, however, immunoblot analysis reveals intense bands of PrPRes in both regions. Similar electrophoretic patterns were observed for the cerebella of all patients. Treatment of extracts with PK and PNGase F (to deglycosylate) generates a pattern similar to that of PK treatment alone. Thus, our findings suggest that, in GSS F198S, brain extracts contain three prominent non-glycosylated PrPRes fragments, forming a pattern not previously described in other prion diseases, which may in part explain the pathology of this GSS variant. In addition, the data indicate that abnormal PrP isoforms accumulate early in the disease and are found in various brain regions including areas with a small amount of amyloid. (PHS NS 29822)
ZR 0
SP englisch
OR Prion-Krankheiten 6