Potent glycan inhibitors of myelin-associated glycoprotein enhance axon outgrowth in Vitro

Alka A. Vyasi, Ola Blixt, James C. Paulson, Ronald Lee Schnaar

Research output: Contribution to journalArticle

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 (NeuAcα2-3Gal/β1-3[NeuAcα2-6] GalNAc-R), followed by 3-sialyl T antigen (NeuAcα2-3Galβ1-3GalNAc-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-α-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.

Original languageEnglish (US)
Pages (from-to)16305-16310
Number of pages6
JournalJournal of Biological Chemistry
Volume280
Issue number16
DOIs
StatePublished - Apr 22 2005

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Myelin-Associated Glycoprotein
Polysaccharides
Axons
Regeneration
Aptitude
Gangliosides
Viral Tumor Antigens
Glycosides
Glycoproteins
Sialic Acid Binding Immunoglobulin-like Lectins
Nervous System Trauma
Central Nervous System Diseases
N-Acetylneuraminic Acid
Lectins
Recovery
Neurology
Neurons
Inhibition (Psychology)
In Vitro Techniques
Neuronal Outgrowth

ASJC Scopus subject areas

  • Biochemistry

Cite this

Potent glycan inhibitors of myelin-associated glycoprotein enhance axon outgrowth in Vitro. / Vyasi, Alka A.; Blixt, Ola; Paulson, James C.; Schnaar, Ronald Lee.

In: Journal of Biological Chemistry, Vol. 280, No. 16, 22.04.2005, p. 16305-16310.

Research output: Contribution to journalArticle

Vyasi, Alka A. ; Blixt, Ola ; Paulson, James C. ; Schnaar, Ronald Lee. / Potent glycan inhibitors of myelin-associated glycoprotein enhance axon outgrowth in Vitro. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 16. pp. 16305-16310.
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N2 - 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 (NeuAcα2-3Gal/β1-3[NeuAcα2-6] GalNAc-R), followed by 3-sialyl T antigen (NeuAcα2-3Galβ1-3GalNAc-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-α-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.

AB - 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 (NeuAcα2-3Gal/β1-3[NeuAcα2-6] GalNAc-R), followed by 3-sialyl T antigen (NeuAcα2-3Galβ1-3GalNAc-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-α-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.

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