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. Epub 2018 Jul 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-alpha Demethylase Inhibitors / pharmacology
  • Animals
  • Cholesterol / biosynthesis
  • HEK293 Cells
  • High-Throughput Screening Assays
  • Humans
  • Imidazoles / pharmacology
  • Male
  • Membrane Proteins / antagonists & inhibitors
  • Mice
  • Mice, Inbred C57BL
  • Multiple Sclerosis
  • Myelin Sheath / metabolism*
  • Oligodendroglia / cytology*
  • Oligodendroglia / drug effects
  • Oligodendroglia / metabolism*
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors
  • Remyelination* / drug effects
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Spinal Cord / drug effects
  • Spinal Cord / pathology
  • Steroid Isomerases / antagonists & inhibitors
  • Sterol 14-Demethylase / metabolism
  • Sterols / chemistry*
  • Sterols / metabolism*
  • Substrate Specificity


  • 14-alpha Demethylase Inhibitors
  • Imidazoles
  • Membrane Proteins
  • Sterols
  • Cholesterol
  • Sterol 14-Demethylase
  • Oxidoreductases Acting on CH-CH Group Donors
  • TM7SF2 protein, human
  • Steroid Isomerases