Myelin-associated glycoprotein and complementary axonal ligands, gangliosides, mediate axon stability in the CNS and PNS: Neuropathology and behavioral deficits in single- and double-null mice

Abstract

Complementary interacting molecules on myelin and axons are required for long-term axon-myelin stability. Their disruption results in axon degeneration, contributing to the pathogenesis of demyelinating diseases. Myelin-associated glycoprotein (MAG), a minor constituent of central and peripheral nervous system myelin, is a member of the Siglec family of sialic acid-binding lectins and binds to gangliosides GD1a and GT1b, prominent molecules on the axon surface. Mice lacking the ganglioside biosynthetic gene Galgt1 fail to express complex gangliosides, including GD1a and GT1b. In the current studies, CNS and PNS histopathology and behavior of Mag-null, Galgt1-null, and double-null mice were compared on the same mouse strain background. When back-crossed to >99% C57BL/6 strain purity, Mag-null mice demonstrated marked CNS, as well as PNS, axon degeneration, in contrast to prior findings using mice of mixed strain background. On the same background, Mag- and Galgt1-null mice exhibited quantitatively and qualitatively similar CNS and PNS axon degeneration and nearly identical decreases in axon diameter and neurofilament spacing. Double-null mice had qualitatively similar changes. Consistent with these findings, Mag- and Galgt1-null mice had similar motor behavioral deficits, with double-null mice only modestly more impaired. Despite their motor deficits, Mag- and Galgt1-null mice demonstrated hyperactivity, with spontaneous locomotor activity significantly above that of wild type mice. These data demonstrate that MAG and complex gangliosides contribute to axon stability in both the CNS and PNS. Similar neuropathological and behavioral deficits in Galgt1-, Mag-, and double-null mice support the hypothesis that MAG binding to gangliosides contributes to long-term axon-myelin stability.

Physiological Exploration of the Long Term Evolutionary Selection against Expression of N-Glycolylneuraminic Acid in the Brain

“…NCmahTg mice exhibited hyperactivity throughout the test time in this study (Fig. 8F), consistent with a previous report showing that Mag-null and B4galnt1-null mice were reported to be hyperactive (49). Basal pain response was also assessed given that it can be mediated by myelinated axons.…”

Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth

“…In support of this perception, it has been reported that a disruption of synthesis of complex gangliosides in axons of mice leads to an interruption of the interaction of gangliosides with complementary lectin-binding partners, e.g., myelin-associated glycoprotein, months after birth (27). In this study, the morphologic sequelae were axon degeneration.…”

Cingulum bundle white matter in MAG-knockout mice

“…There is no indication of any sex-specific effect of the MAG gene [38], so our groups included both sexes. We also included one heterozygote mouse in our wildtype control group, because there is no indication of a heterozygote phenotype [33].…”

“…Selected because of its decreased expression levels [1,2,22] and impaired hindlimb reflex extension [38]. However, the mutant mice showed no differences in spatial learning and memory or in swimming speed, as demonstrated by a Morris water maze test [37].…”