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J. Biol. Chem., Vol. 280, Issue 16, 16305-16310, April 22, 2005

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Potent Glycan Inhibitors of Myelin-associated Glycoprotein Enhance Axon Outgrowth in Vitro^*

Alka A. Vyas, Ola Blixt¶, James C. Paulson¶, and Ronald L. Schnaar||**

From the Departments of Pharmacology and ^||Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205 and Departments of Molecular Biology and ^¶Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

Myelin-associated glycoprotein (MAG, Siglec-4) is one of several endogenous axon regeneration inhibitors that limit recovery from central nervous system injury and disease. Molecules that block such inhibitors may enhance axon regeneration and functional recovery. MAG, a member of the Siglec family of sialic acid-binding lectins, binds to sialoglycoconjugates on axons and particularly to gangliosides GD1a and GT1b, which may mediate some of the inhibitory effects of MAG. In a prior study (Blixt, O., Collins, B. E., van den Nieuwenhof, I. M., Crocker, P. R., and Paulson, J. C. (2003) J. Biol. Chem. 278, 31007-31019), we identified potent monovalent sialoside inhibitors of MAG using a novel screening platform. In the current study, the most potent of these were tested for their ability to reverse MAG-mediated inhibition of axon outgrowth from rat cerebellar granule neurons in vitro. Monovalent sialoglycans enhanced axon regeneration in proportion to their MAG binding affinities. The most potent glycoside was disialyl T antigen (NeuAc2–3Gal1–3[NeuAc2–6]GalNAc-R), followed by 3-sialyl T antigen (NeuAc2–3Gal1–3GalNAc-R), structures expressed on O-linked glycoproteins as well as on gangliosides. Prior studies indicated that blocking gangliosides reversed MAG inhibition (Vyas, A. A., Patel, H. V., Fromholt, S. E., Heffer-Lauc, M., Vyas, K. A., Dang, J., Schachner, M., and Schnaar, R. L. (2002) Proc. Natl. Acad. Sci. USA 99, 8412–8417). In the current study, blocking O-linked glycoprotein sialylation with benzyl--GalNAc had no effect. The ability to reverse MAG inhibition with monovalent glycosides encourages further exploration of glycans and glycan mimetics as blockers of MAG-mediated axon outgrowth inhibition.

Received for publication, January 7, 2005 , and in revised form, February 3, 2005.

^* This work was supported by NINDS Grant NS37096 and NIGMS Grant GM60938 from the National Institutes of Health, United States Public Health Service. 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 should be addressed: Dept. of Pharmacology and Molecular Sciences, The Johns Hopkins School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205. Tel.: 410-955-8392; Fax: 410-955-4900; E-mail: schnaar{at}jhu.edu.

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