Potent glycan inhibitors of myelin-associated glycoprotein enhance axon outgrowth in vitro.
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, 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 (NeuAcalpha2-3Galbeta1-3[NeuAcalpha2-6]GalNAc-R), followed by 3-sialyl T antigen (NeuAcalpha2-3Galbeta1-3GalNAc-R), structures expressed on O-linked glycoproteins as well as on gangliosides. Prior studies indicated that blocking gangliosides reversed MAG inhibition. 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.
Vyas
Alka A
AA
Department of Pharmacology, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
Blixt
Ola
O
Paulson
James C
JC
Schnaar
Ronald L
RL
D000818:Animals; D001369:Axons / Q000502:physiology*; D002531:Cerebellum / Q000378:metabolism; D008024:Ligands; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors*; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism*; D051381:Rats
D008024:Ligands; D018992:Myelin-Associated Glycoprotein; D011134:Polysaccharides; D019158:N-Acetylneuraminic Acid