NR AOQH
AU Ben-Zaken,O.; Tzaban,S.; Tal,Y.; Horonchik,L.; Esko,J.D.; Vlodavsky,I.; Taraboulos,A.
TI The involvement of heparan sulfate in the metabolism of prions
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Oral sessions OS-15
PT Konferenz-Vortrag
AB Previous biochemical, histological and pharmacological data have suggested that glycosaminoglycans (GAGs), and especially heparan sulfate (HS), are involved in the biogenesis and the pathology of prions. PrP has three heparin-binding regions (J. Biol. Chem. 2002, 277, 18421). Here we have investigated the involvement of cellular HS in the metabolism of PrPsc in scrapie-infected ScN2a cells. Xylosides reduce the glycosylation of proteoglycans by competing with the priming of GAG synthesis on the protein core. The lipophilic xyloside EDX reduced protease-resistant PrPsc without affecting PrPc, suggesting that cellular GAGs are involved in the metabolism of PrPsc. To further characterize the types of GAGs involved, we used bacterial and mammalian GAG-degrading enzymes. Incubating ScN2a cells with heparinase III and recombinant human heparanase (but not with heparinase I or chondroitinase ABC) strongly reduced PrPsc. In contrast, neither the level of PrPc, nor its association with detergent-insoluble fractions, were altered in heparinase III-treated cells. In vitro incubation of ScN2a membranes with heparinase III did not decrease the protease-resistance of PrPsc, suggesting that the enzyme did not act directly on the biochemical properties of PrPsc. Chlorate, a metabolic inhibitor of sulfation, vastly reduces PrPsc in ScN2a cells (J. Cell Physiol. 1993, 157, 319). Soluble HS or chondroitin sulfate partially restored PrPsc levels in chlorate-treated cells. Taken together, these results suggest that heparinase III-sensitive cellular HS are involved in the metabolism of PrPsc in ScN2a cells. Additional data and possible mechanisms of action will be discussed.
AD Olga Ben-Zaken, Department of Oncology, Hadassah University Hospital, Jerusalem 91120, Israel; Salit Tzaban, Yuval Tal, Lior Horonchik, Albert Taraboulos, Department of Molecular Biology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Jeffrey D. Esko, Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093; Israel Vlodavsky, Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel
SP englisch
PO Deutschland