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| Potent glycan inhibitors of myelin-associated glycoprotein enhance axon outgrowth in vitro |
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| Author(s): Vyas AA, Blixt O, Paulson JC, Schnaar RL |
| Source: JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 280 Issue: 16 Pages: 16305-16310 Published: APR 22 2005 |
| Times Cited: 21 References: 51 |
| Abstract: 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 (NeuAc alpha 2 - 3Gal beta 1 - 3[NeuAc alpha 2 - 6] GalNAc-R), followed by 3-sialyl T antigen (NeuAc alpha 2 - 3Gal beta 1 - 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-alpha 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Schnaar, RL (reprint author), Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, 725 N Wolfe St, Baltimore, MD 21205 USA |
Addresses:
1. Johns Hopkins Univ, Sch Med, Dept Pharmacol, Baltimore, MD 21205 USA
2. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
3. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
4. Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA |
| Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: 917GO |
| ISSN: 0021-9258 |
| DOI: 10.1074/jbc.M500250200 |
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