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 diseases1,2,3. 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 vivo4,5,6,7,8,9,10. 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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This work was supported by National Institutes of Health grant NS095280 (R.H.M., P.J.T), Conrad N. Hilton Foundation Pilot Innovator in MS Award (D.J.A.), Mallinckrodt Foundation Grant Award (D.J.A.), Mt. Sinai Health Care Foundation, philanthropic support from the Peterson, Fakhouri, Long, Goodman, Geller, Judge, and Weidenthal families, and unrestricted support from the CWRU School of Medicine. Z.H., M.S.E., K.C.A., Z.S.N., and J.L.S. were supported by the CWRU Medical Scientist Training Program (NIH T32 GM007250). Z.H. was also supported by NIH TL1 TR000441. Additional support was provided by the Small-Molecule Drug Development, Proteomics, and Translational Research Shared Resources of the Case Comprehensive Cancer Center (P30 CA043703). We acknowledge use of the Leica SP8 confocal microscope in the Light Microscopy Imaging Facility at CWRU made available through the Office of Research Infrastructure (NIH-ORIP) Shared Instrumentation Grant (S10 OD016164). We thank M. Drumm, T. Miller, B. Karl, O. Iyoha-Bello, J. Pink., P. Conrad, R. Lee, X. Li, D. Schlatzer, K. Polak, Janssen Pharmaceutica N.V., CXR Biosciences, ThermoFisher, Avanti Polar Lipids, and the P. Scacheri laboratory for technical assistance and discussion.