title: Transgenic over-expression of mammalian heparanase delays prion disease onset and progression.
abstract: Cellular heparan sulfate (HS) has a dual role in scrapie pathogenesis; it is required for PrP(Sc) (scrapie prion protein) formation and facilitates infection of cells, mediating cellular uptake of prions. We examined the involvement of heparanase, a mammalian endoglycosidase degrading HS, in scrapie infection. In cultured cells, heparanase treatment or over-expression resulted in a profound decrease in PrP(Sc). Moreover, disease onset and progression were dramatically delayed in scrapie infected transgenic mice over-expressing heparanase. Together, our results provide direct in vivo evidence for the involvement of intact HS in the pathogenesis of prion disease and the protective role of heparanase both in terms of susceptibility to infection and disease progression.
authors.affiliation: Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel; Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, 31096, Haifa, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Kovalchuk Ben-Zaken
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Nissan
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Tzaban
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Taraboulos
authors.affiliation: Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Zcharia
authors.affiliation: Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Matzger
authors.affiliation: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, 31096, Haifa, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Shafat
authors.affiliation: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, 31096, Haifa, Israel. Electronic address: vlodavsk@cc.huji.ac.il.
authors.forename: I
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Tal
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D018450:Disease Progression; D004198:Disease Susceptibility; D005260:Female; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018620:PrPSc Proteins / Q000378:metabolism / Q000472:pathogenicity; D017096:Prion Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012608:Scrapie / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D013997:Time Factors; D015854:Up-Regulation; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D006497:Heparan Sulfate; D018620:PrPSc Proteins; D011994:Recombinant Proteins; D000099175:Heparanase
keywords: Heparan sulfate; Heparanase; Prion disease; Scrapie prion protein; Survival time; Transgenic mice