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Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation

Nature Chemical Biology volume 14, pages 22–28 (2018)Cite this article

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Abstract

Endogenous metabolites play essential roles in the regulation of cellular identity and activity. Here we have investigated the process of oligodendrocyte precursor cell (OPC) differentiation, a process that becomes limiting during progressive stages of demyelinating diseases, including multiple sclerosis, using mass-spectrometry-based metabolomics. Levels of taurine, an aminosulfonic acid possessing pleotropic biological activities and broad tissue distribution properties, were found to be significantly elevated (∼20-fold) during the course of oligodendrocyte differentiation and maturation. When added exogenously at physiologically relevant concentrations, taurine was found to dramatically enhance the processes of drug-induced in vitro OPC differentiation and maturation. Mechanism of action studies suggest that the oligodendrocyte-differentiation-enhancing activities of taurine are driven primarily by its ability to directly increase available serine pools, which serve as the initial building block required for the synthesis of the glycosphingolipid components of myelin that define the functional oligodendrocyte cell state.

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Figure 1: Observed metabolic differences between T3- and DMSO-treated OPCs.
Figure 2: Impact of taurine treatment on the efficacy of drug-induced OPC differentiation.
Figure 3: Impact of taurine treatment on observed indices of MBP colocalization with co-cultured axons.
Figure 4: The impact of taurine treatment on OL mitochondrial function and the role of redox state on OPC differentiation.
Figure 5: Binary global metabolomics analysis of taurine co-treatment and evaluation of the impact of inhibition of taurine biosynthesis on OL differentiation.

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Acknowledgements

We gratefully acknowledge financial support from the National Institutes of Health (Grants R01 GM114368-02, R24 EY017540-04, P30 MH062261-10, P01 DA026146-02, and 1S10OD16357).

Author information

Author notes

  1. Mingliang Fang

    Present address: School of Civil and Environmental Engineering, Nanyang Technological University, Singapore, Singapore

  2. Brittney A Beyer and Mingliang Fang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA

    Brittney A Beyer & Luke L Lairson

  2. The California Institute for Biomedical Research, La Jolla, California, USA

    Brittney A Beyer, Benjamin Sadrian & Warren C Plaisted

  3. Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, La Jolla, California, USA

    Mingliang Fang, J Rafael Montenegro-Burke & Gary Siuzdak

  4. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA

    Bernard P C Kok & Enrique Saez

  5. Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

    Toru Kondo

  6. Department of Molecular and Computational Biology, The Scripps Research Institute, La Jolla, California, USA

    Gary Siuzdak

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Contributions

B.A.B., M.F., G.S. and L.L.L. initiated the project, developed the strategy and generated experimental design. B.A.B., W.C.P. and B.S. performed molecular biology and cell-based experiments. M.F. and J.R.M.-B. performed mass spectrometry and metabolomics experiments. B.P.C.K., B.A.B. and M.F. performed OCR experiments. B.A.B., M.F., W.C.P., B.S., J.R.M.-B., G.S. and L.L.L. interpreted data. E.S. and T.K. contributed essential ideas and comments. B.A.B., M.F., G.S. and L.L.L. wrote the manuscript.

Corresponding authors

Correspondence to Gary Siuzdak or Luke L Lairson.

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The authors declare no competing financial interests.

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Beyer, B., Fang, M., Sadrian, B. et al. Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation. Nat Chem Biol 14, 22–28 (2018). https://doi.org/10.1038/nchembio.2517

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