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 diseases. 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 vivo. 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.
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Date of publication: 25 July 2018; Nature: International Journal of Science
Author information: Zita Hubler (1); Dharmaraja Allimuthu (1); Ilya Bederman (2); Matthew S. Elitt (1); Mayur Madhavan (1); Kevin C. Allan (1); H. Elizabeth Shick (1); Eric Garrison (3); Molly T. Karl (3); Daniel C. Factor (1); Zachary S. Nevin (1); Joel L. Sax (1); Matthew A. Thompson (1); Yuriy Fedorov (4); Jing Jin (5); William K. Wilson (5); Martin Giera (6); Franz Bracher (7); Robert H. Miller (3); Paul J. Tesar (1); & Drew J. Adams (1)
(1) Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
(2) Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
(3) Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
(4) Small Molecule Drug Development Core, Case Western Reserve University School of Medicine, Cleveland, OH, USA
(5) Department of BioSciences, Rice University, Houston, TX, USA
(6) Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, The Netherlands
(7) Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians University of Munich, Munich, Germany