title: Cellular heparan sulfate participates in the metabolism of prions.
abstract: During prion diseases, the host protein PrPC is refolded into an abnormal conformer "prion" PrPSc. 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 PrPSc in prion-infected ScN2a cells. When ScN2a cells were incubated with estradiol beta-d-xyloside to inhibit the glycosylation of proteoglycans, PrPSc was vastly reduced. Treating ScN2a-M cells with heparinase III, but not with heparinase I or chondroitinase ABC, caused a profound reduction of PrPSc. In contrast, neither the amount of PrPC 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 PrPSc. The inhibitor of sulfation, sodium chlorate, vastly reduces PrPSc 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 PrPSc in chlorate-treated cells. We conclude that heparinase III-sensitive, presumably undersulfated, cellular heparan sulfate plays a significant role in the biogenesis of PrPSc in ScN2a cells.
authors.affiliation: Department of Oncology, Hadassah-University Hospital, Jerusalem 91120, Israel.
authors.forename: Olga
authors.initials: O
authors.lastname: Ben-Zaken
authors.forename: Salit
authors.initials: S
authors.lastname: Tzaban
authors.forename: Yuval
authors.initials: Y
authors.lastname: Tal
authors.forename: Lior
authors.initials: L
authors.lastname: Horonchik
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Albert
authors.initials: A
authors.lastname: Taraboulos
mesh_terms: D000818:Animals; D006025:Glycosaminoglycans / Q000378:metabolism; D006027:Glycosides / Q000494:pharmacology; D006031:Glycosylation; D019763:Heparin Lyase / Q000494:pharmacology; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D008954:Models, Biological; D011133:Polysaccharide-Lyases / Q000494:pharmacology; D018621:PrPC Proteins / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism
chemical_list: D006025:Glycosaminoglycans; D006027:Glycosides; D019763:Heparin Lyase; D006497:Heparan Sulfate; D011133:Polysaccharide-Lyases; D018621:PrPC Proteins; D018620:PrPSc Proteins; C010807:xylosides; C021349:heparitinsulfate lyase