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

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. Sax, Matthew A. Thompson, Yuriy Fedorov, Jing Jin, William K. Wilson, Martin Giera, Franz Bracher, Robert H. Miller, Paul J. Tesar and Drew J. Adams ()
Additional contact information
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

Nature, 2018, vol. 560, issue 7718, 372-376

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41586-018-0360-3

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