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J. Biol. Chem., Vol. 280, Issue 11, 10516-10523, March 18, 2005

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Glycosylation-related Gene Expression in Prion Diseases

PrP^Sc ACCUMULATION IN SCRAPIE INFECTED GT1 CELLS DEPENDS ON -1,4-LINKED GalNAc-4-SO₄ HYPOSULFATION^*

Agnès Barret, Lionel Forestier, Jean-Philippe Deslys, Raymond Julien¶, and Paul François Gallet||

From the Groupe d'Innovation Diagnostique et Thérapeutique des Infections à Prions, Commissariat à l'Energie Atomique, 18 route du Panorama, 92265, Fontenay-aux-Roses, France and the Génétique Moléculaire Animale, UMR-INRA 1061, Institut des Sciences de la Vie et de la Santé, 123 avenue Albert Thomas, 87060 Limoges, France

Several lines of evidence indicate that some glycoconjugates are efficient effectors of the cellular prion protein (PrP^C) conversion into its pathogenic (PrP^Sc) isoform. To assess how glycoconjugate glycan moieties participate in the biogenesis of PrP^Sc, an exhaustive comparative analysis of the expression of about 200 glycosylation-related genes was performed on prion-infected or not, hypothalamus-derived GT1 cells by hybridization of DNA microarrays, semiquantitative RT-PCR, and biochemical assays. A significant up- (30-fold) and down- (17-fold) regulation of the expression of the ChGn1 and Chst8 genes, respectively, was observed in prion-infected cells. ChGn1 and Chst8 are involved in the initiation of the synthesis of chondroitin sulfate and in the 4-O-sulfation of non-reducing N-acetylgalactosamine residues, respectively. A possible role for a hyposulfated chondroitin in PrP^Sc accumulation was evidenced at the protein level and by determination of chondroitin and heparan sulfate amounts. Treatment of Sc-GT1 cells with a heparan mimetic (HM2602) induced an important reduction of the amount of PrP^Sc, associated with a total reversion of the transcription pattern of the N-acetylgalactosamine-4-O-sulfotransferase 8. It suggests a link between the genetic control of 4-O-sulfation and PrP^Sc accumulation.

Received for publication, November 8, 2004 , and in revised form, January 4, 2005.

^* This work was supported by grants from the Conseil Regional du Limousin and the Commissariat à l'Energie Atomique (to A. B.) and by the GIS Infections à prions. 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.

¶ To whom correspondence may be addressed. E-mail: rjulien{at}unilim.fr. || To whom correspondence may be addressed. E-mail: francois.gallet{at}unilim.fr.

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