NR APOM
AU Chen,S.G.; Parchi,P.; Brown,P.; Roos,R.P.; Vnencak-Jones,C.L.; Gambetti,P.
TI Fatal familial insomnia and familial Creutzfeldt-Jakob disease - abnormal prion protein (PrPres) encoded by the mutant allele
QU Journal of Neuropathology and Experimental Neurology 1996; 55(N5): 636 Nr. 124
PT Meeting Abstract
VT
FATAL FAMILIAL INSOMNIA AND FAMILIAL CREUTZFEDT-JAKOB DISEASE: ABNORMAL PRION PROTEIN (PRPres) ENCODED BY THE MUTANT ALLELE.
S.G. Chen, P. Parchi, P. Brown, R.P. Roos, C.L. Vnencak-Jones, and P. Gambetti*.
Case Western Reserve University, Cleveland, OH; NINDS, Bethesda, MD; University of Chicago, Chicago, IL; Vanderbilt University, Nashville, TN.
The hallmark of all prion diseases is the presence of PrPres, an abnormal isoform of prion protein that is partially resistant to proteolysis and to solubilization by detergents. PrPres is thought to derive from the normal isoform of PrP, but the underlying molecular mechanisms are unknown. Various mutations in human prion protein gene are linked to familial prion diseases such as fatal familial insomnia (FFI), familial Creutzfedt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome. Most patients with FFI and familial CJD are heterozygous for the mutations, and express both wild type and mutant PrP. To understand the role of the mutant PrP in the formation of PrPres, we have examined protease resistance and detergent solubility of PrP encoded by different alleles. We found that the mutant PrP is more resistant to protease digestion than the wild type PrP. Ultacentrifugation of PrP in non-denaturing detergents revealed that PrP encoded by the mutant allele was recovered in the detergent-insoluble fraction, and was protease-resistant. The PrPres was purified from brains of patients to homogeneity as judged by silver staining of SDS/PAGE. Peptide mapping of PrPres from FFI and CJD178 by endoproteinase Asp-N generated fragments characteristics of PrP with the codon 178 Asp->Asn mutation, showing that PrPres is denived exclusively from the mutant allele. Our data indicate that in FFI and CJD178 only the mutant PrP is converted into PrPres, providing evidence that the mutations predispose PrP to the conversion process. Supported by the National Institutes of Health grants AG-08155 and AG-O8992, and the Britton Fund.
ZR 0 Zitate
SP englisch
OR Prion-Krankheiten C