Myelin-associated glycoprotein activation triggers glutamate uptake by oligodendrocytes in vitro and contributes to ameliorate glutamate-mediated toxicity in vivo

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2022-04, Vol.1868 (4), p.166324, Article 166324
• Main Authors: Vivinetto, Ana L., Castañares, Clara, Garcia-Keller, Constanza, Moyano, Ana Lis, Falcon, Cristian, Palandri, Anabela, Rozés-Salvador, Victoria, Rojas, Juan I., Patrucco, Liliana, Monferran, Clara, Cancela, Liliana, Cristiano, Edgardo, Schnaar, Ronald L., Lopez, Pablo H.H.
• Format: Article
• Language: English
• Subjects: Amino Acid Transport Systems, Acidic - genetics; Amino Acid Transport Systems, Acidic - metabolism; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Axons - metabolism; Cells, Cultured; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - pathology; Excitotoxicity; Experimental autoimmune encephalomyelitis; Glutamate; Glutamic Acid - administration & dosage; Glutamic Acid - metabolism; Glutamic Acid - pharmacology; Glutathione - metabolism; Mice; Mice, Inbred C57BL; Multiple sclerosis; Myelin; Myelin-associated glycoprotein; Myelin-Associated Glycoprotein - immunology; Myelin-Associated Glycoprotein - metabolism; Neurodegeneration; Neurons - metabolism; Neuroprotection; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oligodendrocyte; Oligodendroglia - cytology; Oligodendroglia - metabolism; Oxidative Stress - drug effects; Protein Kinase C - metabolism; Rats; Receptors, Glutamate - metabolism; Signal Transduction - drug effects; Stroke
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2021.166324

Myelin-associated glycoprotein (MAG) is a key molecule involved in the nurturing effect of myelin on ensheathed axons. MAG also inhibits axon outgrowth after injury. In preclinical stroke models, administration of a function-blocking anti-MAG monoclonal antibody (mAb) aimed to improve axon regeneration demonstrated reduced lesion volumes and a rapid clinical improvement, suggesting a mechanism of immediate neuroprotection rather than enhanced axon regeneration. In addition, it has been reported that antibody-mediated crosslinking of MAG can protect oligodendrocytes (OLs) against glutamate (Glu) overload by unknown mechanisms. To unravel the molecular mechanisms underlying the protective effect of anti-MAG therapy with a focus on neuroprotection against Glu toxicity. MAG activation (via antibody crosslinking) triggered the clearance of extracellular Glu by its uptake into OLs via high affinity excitatory amino acid transporters. This resulted not only in protection of OLs but also nearby neurons. MAG activation led to a PKC-dependent activation of factor Nrf2 (nuclear-erythroid related factor-2) leading to antioxidant responses including increased mRNA expression of metabolic enzymes from the glutathione biosynthetic pathway and the regulatory chain of cystine/Glu antiporter system xc− increasing reduced glutathione (GSH), the main antioxidant in cells. The efficacy of early anti-MAG mAb administration was demonstrated in a preclinical model of excitotoxicity induced by intrastriatal Glu administration and extended to a model of Experimental Autoimmune Encephalitis showing axonal damage secondary to demyelination. MAG activation triggers Glu uptake into OLs under conditions of Glu overload and induces a robust protective antioxidant response. [Display omitted] •MAG activation in Oligodendrocytes induces extracellular glutamate uptake.•MAG activation in Oligodendrocytes results in a PLC/PKC-mediated activation of Nfr2 leading to an antioxidant response.•MAG activation results in neuroprotection against glutamate-mediated toxicity in vivo.