The BHMT-TET1 axis regulates glycolytic metabolism in oligodendrocytes and increases myelin in the EAE mouse model of multiple sclerosis

Shalih Maraicar, M.; Sternbach, S.; Psenicka, M. W.; Knies, K.; Lesco, E.; Ramel, N. A.; Eagar, A.; Zeisel, S.; Freeman, E. J.; Clements, R.; Williams, J. L.; McDonough, J.

doi:10.64898/2026.07.22.737014

bioRxiv · 10.64898/2026.07.22.737014

The BHMT-TET1 axis regulates glycolytic metabolism in oligodendrocytes and increases myelin in the EAE mouse model of multiple sclerosis

Shalih Maraicar, M.·Sternbach, S.·Psenicka, M. W.·Knies, K.·Lesco, E.·Ramel, N. A.·Eagar, A.·Zeisel, S.·Freeman, E. J.·Clements, R.·Williams, J. L.·McDonough, J.

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Abstract

The inability of oligodendrocyte progenitor cells (OPCs) to mature into myelin-making oligodendrocytes (OLs) is a major contributor to disease and disability in multiple sclerosis (MS). Oligodendrocyte maturation is a tightly controlled process with a strong reliance on epigenetic regulation involving DNA methylation and hydroxymethylation. We have previously shown that one carbon metabolism is dysregulated in MS, specifically the methyl donor betaine is depleted in the MS brain. Betaine donates methyl groups to betaine homocysteine methyltransferase (BHMT) in the methionine cycle to increase S-adenosylmethionine (SAM) for epigenetic methylation processes. In the present study we tested the effects of activating the BHMT methylation pathway on preventing MS pathology. We describe a novel mechanism mediated by BHMT and the Ten-eleven translocator enzyme (TET1) that converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). We show that this pathway supports oligodendrocyte metabolism to enhance myelin and reduce clinical disability in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. ChIP-seq studies show that BHMT is enriched at genes involved in OPC metabolism and proximal ligation assays (PLAs) demonstrate that BHMT interacts with TET1 on chromatin. This interaction regulates gene expression programs that support a shift in OPC metabolism to glycolysis during neuroinflammatory processes. These data highlight the critical role of methionine metabolism in supporting myelination and have important implications for the development of new therapeutic strategies for MS and other neurodegenerative diseases.

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Shalih Maraicar, M., Sternbach, S., Psenicka, M. W., Knies, K., Lesco, E., Ramel, N. A., Eagar, A., Zeisel, S., Freeman, E. J., Clements, R., Williams, J. L., McDonough, J.. 2026-07-27. The BHMT-TET1 axis regulates glycolytic metabolism in oligodendrocytes and increases myelin in the EAE mouse model of multiple sclerosis. https://doi.org/10.64898/2026.07.22.737014

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