Myelin‐associated glycoprotein protects neurons from excitotoxicity

Abstract

J. Neurochem. (2011) 116, 900–908. Abstract In addition to supporting rapid nerve conduction, myelination nurtures and stabilizes axons and protects them from acute toxic insults. One myelin molecule that protects and sustains axons is myelin‐associated glycoprotein (MAG). MAG is expressed on the innermost wrap of myelin, apposed to the axon surface, where it interacts with axonal receptors that reside in lateral membrane domains including gangliosides, the glycosylphosphatidylinositol‐anchored Nogo receptors, and β1‐integrin. We report here that MAG protection extends beyond the axon to the neurons from which those axons emanate, protecting them from excitotoxicity. Compared to wild type mice, Mag‐null mice displayed markedly increased seizure activity in response to intraperitoneal injection of kainic acid, an excitotoxic glutamate receptor agonist. Mag‐null mice also had larger lesion volumes in response to intrastriatal injection of the excitotoxin NMDA. Prior injection of a soluble form of MAG partially protected Mag‐null mice from NMDA‐induced lesions. Hippocampal neurons plated on proteins extracted from wild‐type rat or mouse myelin were resistant to kainic acid‐induced excitotoxicity, whereas neurons plated on proteins from Mag‐null myelin were not. Protection was reversed by anti‐MAG antibody and replicated by addition of soluble MAG. MAG‐mediated protection from excitotoxicity was dependent on Nogo receptors and β1‐integrin. We conclude that MAG engages membrane‐domain resident neuronal receptors to protect neurons from excitotoxicity, and that soluble MAG mitigates excitotoxic damage in vivo.

Mice lacking Gpr37 exhibit decreased expression of the myelin-associated glycoprotein MAG and increased susceptibility to demyelination

“…MAG-deficient mice exhibit a modest myelination phenotype (Li et al, 1994; Montag et al, 1994) and only exhibit more dramatic impairments following insults such as toxin treatment, aging or induced demyelination (Jones et al, 2013; Lassmann et al, 1997; Lopez et al, 2011; Weiss et al, 2000). Given the striking decrease in MAG expression that we observed in mice lacking GPR37, we assessed the susceptibility of these mice to demyelination induced by cuprizone.…”

“…MAG is known to promote the stability of myelinated axons (Li et al, 1998; Marcus et al, 2002), and loss of MAG in mouse models results in a modest myelination phenotype (Li et al 1994, Montag et al, 1994) unless the mice are challenged with insults such as toxin treatment, aging, or induced demyelination (Jones et al 2013, Lassman et al 1997, Lopez et al 2011, Weiss et al 2000). However, the mechanisms through which MAG mediates these effects are incompletely understood.…”

Grey and white matter abnormalities in temporal lobe epilepsy with and without mesial temporal sclerosis

“…In contrast to TLE-no whose seizures typically start in early adulthood or later life, TLE-mts already start having recurrent seizures in childhood or adolescence, i.e., at an age when the brain myelination is still ongoing and thus is likely to be negatively affected by seizures and seizure spread. The notion that white matter is better protected against the effects of seizures after the completion of the myelination is supported by animal models that demonstrated a protective effect of the myelin associated glycoprotein against the excitotoxic effects of kainate induced seizures [24]. (4) TLE-no have a different histopathological correlate for their epilepsy than TLE-mts.…”

hnRNP A1 and secondary structure coordinate alternative splicing of Mag

“…MAG has several functions, including inhibition of axon outgrowth and regeneration (McKerracher et al 1994;Mukhopadhyay et al 1994), protecting neurons from excitation-induced toxicity (Lopez et al 2011), and protecting neurons from age-related degeneration (Lassmann et al 1997). Although it is largely normal, the nervous system of Mag-deficient mice has several subtle defects, such as decreased axon diameter and an increased number of unmyelinated axons (Li et al 1994;Montag et al 1994;Bartsch et al 1997;Yin et al 1998).…”

“…Although it is largely normal, the nervous system of Mag-deficient mice has several subtle defects, such as decreased axon diameter and an increased number of unmyelinated axons (Li et al 1994;Montag et al 1994;Bartsch et al 1997;Yin et al 1998). The mice also exhibit age-related axonal degeneration (Lassmann et al 1997) and enhanced excitotoxicity (Lopez et al 2011). MAG interacts with several receptors on the surface of the axon, including ganglioside receptors (GD1a and GT1b) (Yang et al 1996), Nogo receptors (Liu et al 2002;Venkatesh et al 2005), and the paired immunoglobulin-like receptor B (PIR-B) (Atwal et al 2008).…”