Brain gangliosides: Functional ligands for myelin stability and the control of nerve regeneration

Gangliosides, sialylated glycosphingolipids which are the predominant glyca ns on vertebrate nerve cell surfaces, are emerging as components of membran e rafts, where they can mediate important physiological functions. Myelin a ssociated glycoprotein (MAG), a minor constituent of myelin, is a sialic ac id binding lectin with two established physiological functions: it is invol ved in myelin-axon stability and cytoarchitecture, and controls nerve regen eration. MAG is found selectively on the myelin membranes directly apposed to the axon surface, where it has been proposed to mediate myelin-axon inte ractions. Although the nerve cell surface ligands for MAG remain to be esta blished, evidence supports a functional role for sialylated glycoconjugates . Here we review recent studies that reflect on the role of gangliosides, s ialylated glycosphingolipids, as functional MAG ligands. MAG binds to gangl iosides with the terminal sequence 'NeuAc alpha 3Gal beta 3GalNAc' which is found on the major nerve gangliosides GD1a and GT1b. Gangliosides lacking that terminus (e.g., GM1 or GD1b), or having any biochemical modification o f the terminal NeuAc residue fail to support MAG binding. Genetically engin eered mice lacking the GalNAc transferase required for biosynthesis of the 'NeuAca3Gal beta 3GalNAc' terminus have grossly impaired myelination and pr ogressive neurodegeneration. Notably the MAG level in these animals is dysr egulated. Furthermore, removal of NeuAc residues from nerve cells reverses MAG-mediated inhibition of neuritogenesis, and neurons from mice lacking th e 'NeuAca3Gal beta 3GalNAc' terminus have an attenuated response to MAG. Cr oss-linking nerve cell surface gangliosides can mimic MAG-mediated inhibiti on of nerve regeneration. Taken together these observations implicate gangl iosides as functional MAG ligands. (C) 2001 Societe francaise de biochimie et biologie moleculaire Editions scientifiques et medicales Elsevier SAS. A ll rights reserved.