MAG AS A THERAPEUTIC TARGET FOR NEURODEGENERATIVE DISEASES ASSOCIATED TO GLUTAMATE OVERLOAD

CASTAÑARES CN; SCHNAAR RL; MOYANO AL; VIVINETTO AL; LOPEZ PHH

Villa Carlos Paz

Congreso; XXXIV Reunión Anual de la SAN (Sociedad Argentina de Investigación en Neurociencias); 2019

Sociedad Argentina de Investigación en Neurociencias

The aim of our work is to study the protective effect of oligodendrocytes (OLs) against glutamate (Glu) overload, focusing on their key role as critical modulators of extracellular glutamate (eGlu) in white matter. Our group has previously described that mAb-mediated crosslinking/activation of MAG triggers a phosphoinositides/PKC-dependent intracellular signaling which results in reduced oxidative stress and protection of OLs and nearby neurons against Glu overload. By using a fluorimetry-based technique we confirmed that long term antibody-mediated activation of MAG triggers eGlu uptake by OLs. (Fig 1) In the hunt for novel therapeutic bioactive ligands of MAG derived from the structure of its axonal receptors, we tested soluble chimeric forms of its receptors in their ability to trigger an increase in reduced glutathione (GSH) content, evidenced by staining of OLs with the dye monochlorobimane. (Fig 2) We tested commercially available IgG Fc fragment-bound chimeras of receptors NgR1, LRP1, PirB and synthetized covalently-linked ganglioside GT1b-BSA derivatives. GT1b-BSA induced a potent increase of GSH by OLs, while no effect was observed with the structurally-related ganglioside GM3-BSA complex, carrying the common epitope sialyl(α2-3)Gal terminal residue. A weak eGlu uptake was observed when testing other soluble receptors. Altogether, these studies can contribute to the development of novel neuroprotective therapies in order to mitigate neurodegeneration associated with Glu toxicity.