EAAT3 modulation: A potential novel avenue towards remyelination in multiple sclerosis

Abstract

Modulating the excitatory amino acid transporter 3 (EAAT3) can be considered a novel approach for the treatment of multiple sclerosis (MS). EAAT3 plays a crucial role in regulating oxidative stress and oligodendrocyte function through its ability to transport cysteine, the rate-limiting building block in the synthesis of the antioxidant glutathione. Therefore, EAAT3 activation is hypothesised to improve oligodendrocyte health and relieve its differentiation block in MS, improving remyelination capacity. Using a cuprizone-induced demyelination model, the effects of EAAT3 overexpression by viral transduction of oligodendrocytes and pharmacological inhibition of EAAT3 were examined. Surprisingly, EAAT3 overexpression significantly hampered remyelination, while EAAT3 inhibition prevented demyelination and improved functional remyelination as assessed by visual evoked potentials and post mortem myelin basic protein fluorescent staining. Next, cellular mechanisms underlying these results were investigated. Consistent with the in vivo findings, post mortem gene expression analysis of the corpus callosum of cuprizone treated animals revealed a trend towards upregulation of oligodendrocyte lineage genes in response to EAAT3 inhibition, supporting its role in oligodendrocyte health and myelination processes. In vitro studies using the human oligodendroglioma (HOG) cell line demonstrated the beneficial effects of EAAT3 inhibition on cellular morphology, indicating potential roles in promoting oligodendrocyte maturation and myelination. In contrast, EAAT3 overexpression appears to hamper these processes. These findings suggest that, contrary to our initial hypothesis, EAAT3 inhibition could improve oligodendrocyte function and myelination processes, highlighting its potential as a therapeutic target for demyelinating disorders. Future studies should address the exact molecular mechanism through which this effect is obtained.

Keywords: Cysteine; EAAT3; Glutamate; Multiple sclerosis; Neurodegeneration; Oligodendrocytes.