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Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination

Author

Listed:
  • Zita Hubler

    (Case Western Reserve University School of Medicine)

  • Dharmaraja Allimuthu

    (Case Western Reserve University School of Medicine)

  • Ilya Bederman

    (Case Western Reserve University School of Medicine)

  • Matthew S. Elitt

    (Case Western Reserve University School of Medicine)

  • Mayur Madhavan

    (Case Western Reserve University School of Medicine)

  • Kevin C. Allan

    (Case Western Reserve University School of Medicine)

  • H. Elizabeth Shick

    (Case Western Reserve University School of Medicine)

  • Eric Garrison

    (George Washington University School of Medicine and Health Sciences)

  • Molly Karl

    (George Washington University School of Medicine and Health Sciences)

  • Daniel C. Factor

    (Case Western Reserve University School of Medicine)

  • Zachary S. Nevin

    (Case Western Reserve University School of Medicine)

  • Joel L. Sax

    (Case Western Reserve University School of Medicine)

  • Matthew A. Thompson

    (Case Western Reserve University School of Medicine)

  • Yuriy Fedorov

    (Case Western Reserve University School of Medicine)

  • Jing Jin

    (Rice University)

  • William K. Wilson

    (Rice University)

  • Martin Giera

    (Leiden University Medical Center, Center for Proteomics and Metabolomics)

  • Franz Bracher

    (Ludwig-Maximilians University of Munich)

  • Robert H. Miller

    (George Washington University School of Medicine and Health Sciences)

  • Paul J. Tesar

    (Case Western Reserve University School of Medicine)

  • Drew J. Adams

    (Case Western Reserve University School of Medicine)

Abstract

Regeneration of myelin is mediated by oligodendrocyte progenitor cells—an abundant stem cell population in the central nervous system (CNS) and the principal source of new myelinating oligodendrocytes. Loss of myelin-producing oligodendrocytes in the CNS underlies a number of neurological diseases, including multiple sclerosis and diverse genetic diseases1–3. High-throughput chemical screening approaches have been used to identify small molecules that stimulate the formation of oligodendrocytes from oligodendrocyte progenitor cells and functionally enhance remyelination in vivo4–10. Here we show that a wide range of these pro-myelinating small molecules function not through their canonical targets but by directly inhibiting CYP51, TM7SF2, or EBP, a narrow range of enzymes within the cholesterol biosynthesis pathway. Subsequent accumulation of the 8,9-unsaturated sterol substrates of these enzymes is a key mechanistic node that promotes oligodendrocyte formation, as 8,9-unsaturated sterols are effective when supplied to oligodendrocyte progenitor cells in purified form whereas analogous sterols that lack this structural feature have no effect. Collectively, our results define a unifying sterol-based mechanism of action for most known small-molecule enhancers of oligodendrocyte formation and highlight specific targets to propel the development of optimal remyelinating therapeutics.

Suggested Citation

  • Zita Hubler & Dharmaraja Allimuthu & Ilya Bederman & Matthew S. Elitt & Mayur Madhavan & Kevin C. Allan & H. Elizabeth Shick & Eric Garrison & Molly Karl & Daniel C. Factor & Zachary S. Nevin & Joel L, 2018. "Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination," Nature, Nature, vol. 560(7718), pages 372-376, August.
  • Handle: RePEc:nat:nature:v:560:y:2018:i:7718:d:10.1038_s41586-018-0360-3
    DOI: 10.1038/s41586-018-0360-3
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    Cited by:

    1. Irene Molina-Gonzalez & Rebecca K. Holloway & Zoeb Jiwaji & Owen Dando & Sarah A. Kent & Katie Emelianova & Amy F. Lloyd & Lindsey H. Forbes & Ayisha Mahmood & Thomas Skripuletz & Viktoria Gudi & Jame, 2023. "Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Jean-Baptiste Huré & Louis Foucault & Litsa Maria Ghayad & Corentine Marie & Nicolas Vachoud & Lucas Baudouin & Rihab Azmani & Natalija Ivjanin & Alvaro Arevalo-Nuevo & Morgane Pigache & Lamia Bouslam, 2024. "Pharmacogenomic screening identifies and repurposes leucovorin and dyclonine as pro-oligodendrogenic compounds in brain repair," Nature Communications, Nature, vol. 15(1), pages 1-24, December.

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