Gangliosides are neuronal ligands for myelin-associated glycoprotein.

Abstract

Nerve Nerve cell function depends upon appropriate contacts between the neuron and other cells in its immediate environment (1). These include specialized glial cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system, which ensheathe the neuronal axon with myelin, an insulating structure of multilayered membranes (2). Myelin is required for efficient nerve impulse conduction but has other profound biological effects. The inability of nerves to regenerate after CNS injury in adults may be due largely to the axon's inability to grow when in contact with CNS myelin (3, 4). Identification of the cell-surface constituents on neuronal axons and myelin membranes that interact with each other to control cell behavior may facilitate efforts to enhance nerve regeneration as well as modulate myelination.Myelin-associated glycoprotein (MAG), a quantitatively minor protein constituent of CNS (1%) and peripheral nervous system (0.1%) myelin, is implicated in myelin-axonThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.interactions based on its in vivo location and in vitro binding properties. In the CNS, MAG is located exclusively on myelin membranes juxtaposed to axons, where it contributes to maintenance of the periaxonal cytoplasmic collar (5). Purified MAG incorporated into liposomes binds specifically to neuronal processes in cell culture (6)(7)(8). This binding is blocked by an anti-MAG monoclonal antibody (mAb 513) that also inhibits neuron-oligodendrocyte adhesion in vitro (7).One consequence of MAG-axon binding is inhibition of neurite outgrowth from CNS neurons. Cultured primary CNS neurons fail to extend neurites on a substratum of MAGexpressing CHO cells, whereas neurite extension proceeds readily on cells transfected with the reverse (control) construct (9). Recombinant MAG adsorbed to a culture surface inhibits neurite outgrowth from neuroblastoma cells in culture, as does a mixture of detergent-solubilized myelin proteins (10). Immunodepletion of MAG from the solubilized myelin proteins reduces their neurite outgrowth inhibitory activity by more than half. These data implicate MAG as a major neurite outgrowth inhibitory factor in myelin. If true, axonal ligands for MAG may be key elements controlling nerve regeneration in the CNS.

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

“…These results show that clustering specific gangliosides in the absence of Mag and/or Ngr is sufficient to effect inhibition. Undoubtedly, Mag can and does bind gangliosides in a highly specific manner 107 . Indeed, binding to gangliosides is likely to potentiate and augment Mag's effect by inducing clustering of the signalling molecules.…”

Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration

“…This terminal structure is found on some O-linked glycoproteins throughout the body, but in the mammalian brain it is much more abundant on gangliosides GD1a and GT1b (12). Direct binding studies confirmed potent and highly specific MAG binding to these gangliosides (14,34). Furthermore, mice engineered to lack the ''NeuAc ␣3 Gal ␤3 GalNAc'' terminus on gangliosides (but not on glycoproteins) displayed axon degeneration and dysmyelination similar to mice lacking MAG (15).…”

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

“…Neuronal gangliosides mediate communication between axons and myelin-producing cells (23)(24)(25). MAG, a myelin-associated protein found on the myelin membrane adjacent to the axon, interacts with neuronal gangliosides to stabilize axonal-myelin interactions.…”