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

  • Nature. 2018 Aug;560(7718):372-376. doi: 10.1038/s41586-018-0360-3.
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  8
Affiliations
  • 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.
  • 8. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA. [email protected].
PMID: 30046109 DOI: 10.1038/s41586-018-0360-3
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.

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