title: Myelin-associated glycoprotein protects neurons from excitotoxicity.
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.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Pablo H H
authors.initials: PH
authors.lastname: Lopez
authors.forename: Abdullah S
authors.initials: AS
authors.lastname: Ahmad
authors.forename: Niraj R
authors.initials: NR
authors.lastname: Mehta
authors.forename: Mayu
authors.initials: M
authors.lastname: Toner
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Rowland
authors.forename: Jiangyang
authors.initials: J
authors.lastname: Zhang
authors.forename: Sylvain
authors.initials: S
authors.lastname: Doré
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Schnaar
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D039641:Integrin beta Chains / Q000276:immunology; D007608:Kainic Acid / Q000633:toxicity*; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000494:pharmacology; D018992:Myelin-Associated Glycoprotein; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D054801:Phosphoinositide Phospholipase C / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000627:therapeutic use*; D012640:Seizures / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014404:Tubulin / Q000378:metabolism
chemical_list: D000906:Antibodies; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D039641:Integrin beta Chains; C104739:Mag protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; C509624:NEP1-40 protein, human; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D014404:Tubulin; C462941:beta3 tubulin, mouse; D016202:N-Methylaspartate; D054801:Phosphoinositide Phospholipase C; D007608:Kainic Acid