Myelin-associated glycoprotein activation triggers glutamate uptake by oligodendrocytes and mitigates excitotoxicity

VIVINETTO A.; GARCIA KELLER, C; PALANDRI A.; CRISTIAN FALCON; CASTAÑARES CLARA; MOYANO A. L.; ROZES SALVADOR V.; ROJAS J.; PATRUCCO L.; MONFERRAN C; CANCELA LILIANA M; CRISTIANO E; SCHNAAR R; LOPEZ P.

BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2019

0925-4439

BACKGROUND: Myelin-associated glycoprotein (MAG) is a keymolecule involved in the nurturing effect of myelin on ensheathed axons.MAG also inhibits axon outgrowth after injury. In preclinical strokemodels, administration of a function-blocking anti-MAG monoclonalantibody (mAb) aimed to improve axon regeneration demonstrated reducedlesion volumes and a rapid clinical improvement, suggesting a mechanismof immediate neuroprotection rather than enhanced axon regeneration. Inaddition, it has been reported that antibody-mediated crosslinking of MAGcan protect oligodendrocytes (OLs) against glutamate (Glu) overload byunknown mechanisms. PURPOSE: To unravel the molecular mechanismsunderlying the protective effect of anti-MAG therapy with a focus onneuroprotection against Glu toxicity. RESULTS: MAG activation (viaantibody crosslinking) triggered the clearance of extracellular Glu byits uptake into OLs via high affinity excitatory amino acid transporters.This resulted not only in protection of OLs but also nearby neurons. MAGactivation led to a PKC-dependent activation of factor Nrf2 (nuclearerythroidrelated factor-2) leading to antioxidant responses includingincreased mRNA expression of metabolic enzymes from the glutathionebiosynthetic pathway and the regulatory chain of cystine/Glu antiportersystem xc- resulting in an increase in reduced glutathione (GSH), themain antioxidant in cells. The efficacy of early anti-MAG mAbadministration was demonstrated in a preclinical model of excitotoxicityinduced by intrastriatal Glu administration and extended to a model ofExperimental Autoimmune Encephalitis showing axonal damage secondary todemyelination. CONCLUSIONS: MAG activation triggers Glu uptake into OLsunder conditions of Glu overload and induces a robust protectiveantioxidant response.