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J. Biol. Chem., Vol. 278, Issue 41, 40041-40049, October 10, 2003

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Cellular Heparan Sulfate Participates in the Metabolism of Prions^*

Olga Ben-Zaken  , Salit Tzaban  ¶, Yuval Tal ¶, Lior Horonchik ¶, Jeffrey D. Esko ||, Israel Vlodavsky ** and Albert Taraboulos ¶ 

From the Department of Oncology, Hadassah-University Hospital, Jerusalem 91120, Israel, ^¶Department of Molecular Biology, The Hebrew University Hadassah Medical School, Jerusalem 91120, Israel, ^||Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093, and ^**Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel

During prion diseases, the host protein PrP^C is refolded into an abnormal conformer "prion" PrP^Sc. Histological and pharmacological data have suggested that glycosaminoglycans may be involved in the development of prion diseases. Here we present the first direct evidence that cellular glycosaminoglycans play a role in the biogenesis of PrP^Sc in prion-infected ScN2a cells. When ScN2a cells were incubated with estradiol -D-xyloside to inhibit the glycosylation of proteoglycans, PrP^Sc was vastly reduced. Treating ScN2a-M cells with heparinase III, but not with heparinase I or chondroitinase ABC, caused a profound reduction of PrP^Sc. In contrast, neither the amount of PrP^C nor its subcellular distribution were affected as assayed by immunofluorescence microscopy and flotation procedures. In vitro treatment of ScN2a membranes with heparinase III at either neutral or acidic pH did not reduce the level of protease-resistant PrP^Sc. The inhibitor of sulfation, sodium chlorate, vastly reduces PrP^Sc in ScN2a cells (Gabizon, R., Meiner, Z., Halimi, M., and Ben-Sasson, S. A. (1993) J. Cell. Physiol. 157, 319–325). Both soluble heparan sulfate and chondroitin sulfate partially restored the level of PrP^Sc in chlorate-treated cells. We conclude that heparinase III-sensitive, presumably undersulfated, cellular heparan sulfate plays a significant role in the biogenesis of PrP^Sc in ScN2a cells.

Received for publication, February 3, 2003 , and in revised form, July 15, 2003.

^* This work was supported by generous grants from the Israeli Center for the Study of Emerging Diseases (to I. V. and A. T.) and Grants CA46462 and GM33063 from the National Institutes of Health (to J. D. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed. Tel.: 972-2-6757215; Fax: 972-2-6757086; E-mail: taraboul{at}cc.huji.ac.il.

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