Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

The landscape of targets and lead molecules for remyelination

Nature Chemical Biology volume 18, pages 925–933 (2022)Cite this article

Subjects

Abstract

Remyelination, or the restoration of myelin sheaths around axons in the central nervous system, is a multi-stage repair process that remains a major need for millions of patients with multiple sclerosis and other diseases of myelin. Even into adulthood, rodents and humans can generate new myelin-producing oligodendrocytes, leading to the therapeutic hypothesis that enhancing remyelination could lessen disease burden in multiple sclerosis. Multiple labs have used phenotypic screening to identify dozens of drugs that enhance oligodendrocyte formation, and several hit molecules have now advanced to clinical evaluation. Target identification studies have revealed that a large majority of these hits share the ability to inhibit a narrow range of cholesterol pathway enzymes and thereby induce cellular accumulation of specific sterol precursors to cholesterol. This Perspective surveys the recent fruitful intersection of chemical biology and remyelination and suggests multiple approaches toward new targets and lead molecules to promote remyelination.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The tissue response to myelin injury requires the coordination of various cells and signals.
Fig. 2: A general assay flow chart for identifying small-molecule enhancers of remyelination.
Fig. 3: The cholesterol biosynthesis pathway.

Similar content being viewed by others

References

  1. Lubetzki, C., Zalc, B., Williams, A., Stadelmann, C. & Stankoff, B. Remyelination in multiple sclerosis: from basic science to clinical translation. Lancet Neurol. 19, 678–688 (2020).

    Article  PubMed  Google Scholar 

  2. Cunniffe, N. & Coles, A. Promoting remyelination in multiple sclerosis. J. Neurol. 268, 30–44 (2021).

    Article  PubMed  Google Scholar 

  3. Fancy, S. P. et al. Overcoming remyelination failure in multiple sclerosis and other myelin disorders. Exp. Neurol. 225, 18–23 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Hoftberger, R. & Lassmann, H. Inflammatory demyelinating diseases of the central nervous system. Handb. Clin. Neurol. 145, 263–283 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lin, W., Harding, H. P., Ron, D. & Popko, B. Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-γ. J. Cell Biol. 169, 603–612 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Baxi, E. G. et al. Transfer of myelin-reactive Th17 cells impairs endogenous remyelination in the central nervous system of cuprizone-fed mice. J. Neurosci. 35, 8626–8639 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kirby, L. et al. Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination. Nat. Commun. 10, 3887 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Saez-Atienzar, S. et al. Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types. Sci Adv. 7, eabd9036 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kang, S. H. et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat. Neurosci. 16, 571–579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hakak, Y. et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc. Natl Acad. Sci. USA 98, 4746–4751 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen, J. F. et al. Enhancing myelin renewal reverses cognitive dysfunction in a murine model of Alzheimer’s disease. Neuron 109, 2292–2307 e2295 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Siokas, V. et al. Myelin-associated oligodendrocyte basic protein rs616147 polymorphism as a risk factor for Parkinson’s disease. Acta Neurol. Scand. 145, 223–228 (2022).

    Article  CAS  PubMed  Google Scholar 

  13. Perlman, S. J. & Mar, S. Leukodystrophies. Adv. Exp. Med Biol. 724, 154–171 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Olmos-Serrano, J. L. et al. Down syndrome developmental brain transcriptome reveals defective oligodendrocyte differentiation and myelination. Neuron 89, 1208–1222 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang, J. et al. Robust myelination of regenerated axons induced by combined manipulations of GPR17 and Microglia. Neuron 108, 876–886 e874 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bonfanti, E. et al. The role of oligodendrocyte precursor cells expressing the GPR17 receptor in brain remodeling after stroke. Cell Death Dis. 8, e2871 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Back, S. A. et al. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J. Neurosci. 21, 1302–1312 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Plemel, J. R. et al. Mechanisms of lysophosphatidylcholine-induced demyelination: a primary lipid disrupting myelinopathy. Glia 66, 327–347 (2018).

    Article  PubMed  Google Scholar 

  19. Matsushima, G. K. & Morell, P. The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol. 11, 107–116 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Ludwin, S. K. Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab Invest. 39, 597–612 (1978).

    CAS  PubMed  Google Scholar 

  21. Hooijmans, C. R. et al. Remyelination promoting therapies in multiple sclerosis animal models: a systematic review and meta-analysis. Sci. Rep. 9, 822 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Duncan, I. D., Brower, A., Kondo, Y., Curlee, J. F. Jr. & Schultz, R. D. Extensive remyelination of the CNS leads to functional recovery. Proc. Natl Acad. Sci. USA 106, 6832–6836 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Caprariello, A. V., Mangla, S., Miller, R. H. & Selkirk, S. M. Apoptosis of oligodendrocytes in the central nervous system results in rapid focal demyelination. Ann. Neurol. 72, 395–405 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Traka, M., Podojil, J. R., McCarthy, D. P., Miller, S. D. & Popko, B. Oligodendrocyte death results in immune-mediated CNS demyelination. Nat. Neurosci. 19, 65–74 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Glatigny, S. & Bettelli, E. Experimental autoimmune encephalomyelitis (EAE) as animal models of multiple sclerosis (MS). Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a028977 (2018).

  26. Robinson, S. & Miller, R. H. Contact with central nervous system myelin inhibits oligodendrocyte progenitor maturation. Dev. Biol. 216, 359–368 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Kotter, M. R., Li, W. W., Zhao, C. & Franklin, R. J. Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J. Neurosci. 26, 328–332 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Levine, J. M. & Reynolds, R. Activation and proliferation of endogenous oligodendrocyte precursor cells during ethidium bromide-induced demyelination. Exp. Neurol. 160, 333–347 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Wang, Z., Colognato, H. & Ffrench-Constant, C. Contrasting effects of mitogenic growth factors on myelination in neuron-oligodendrocyte co-cultures. Glia 55, 537–545 (2007).

    Article  PubMed  Google Scholar 

  30. Zuchero, J. B. et al. CNS myelin wrapping is driven by actin disassembly. Dev. Cell 34, 152–167 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Franklin, R. J. & Hinks, G. L. Understanding CNS remyelination: clues from developmental and regeneration biology. J. Neurosci. Res. 58, 207–213 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Fancy, S. P., Chan, J. R., Baranzini, S. E., Franklin, R. J. & Rowitch, D. H. Myelin regeneration: a recapitulation of development. Annu Rev. Neurosci. 34, 21–43 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Narayanan, S. P., Flores, A. I., Wang, F. & Macklin, W. B. Akt signals through the mammalian target of rapamycin pathway to regulate CNS myelination. J. Neurosci. 29, 6860–6870 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sim, F. J., Zhao, C., Penderis, J. & Franklin, R. J. The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. J. Neurosci. 22, 2451–2459 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Keough, M. B. et al. An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination. Nat. Commun. 7, 11312 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mozafari, S., Sherafat, M. A., Javan, M., Mirnajafi-Zadeh, J. & Tiraihi, T. Visual evoked potentials and MBP gene expression imply endogenous myelin repair in adult rat optic nerve and chiasm following local lysolecithin induced demyelination. Brain Res. 1351, 50–56 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Green, A. J. et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet 390, 2481–2489 (2017). A milestone for the remyelination field, this paper documented positive results from a randomized controlled trial of clemastine showing improved visual function in patients with MS who have chronic demyelinating optic neuropathy.

    Article  CAS  PubMed  Google Scholar 

  38. Mei, F. et al. Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. eLife 5, e18246 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Duncan, I. D., Marik, R. L., Broman, A. T. & Heidari, M. Thin myelin sheaths as the hallmark of remyelination persist over time and preserve axon function. Proc. Natl Acad. Sci. USA 114, 9685–9691 (2017).

    Article  Google Scholar 

  40. Pearse, D. D. et al. Transplantation of Schwann cells and/or olfactory ensheathing glia into the contused spinal cord: survival, migration, axon association, and functional recovery. Glia 55, 976–1000 (2007).

    Article  PubMed  Google Scholar 

  41. Saab, A. S. et al. Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron 91, 119–132 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Irvine, K. A. & Blakemore, W. F. Remyelination protects axons from demyelination-associated axon degeneration. Brain 131, 1464–1477 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Bodini, B. et al. Dynamic imaging of individual remyelination profiles in multiple sclerosis. Ann. Neurol. 79, 726–738 (2016). The myelin-targeted in vivo human imaging here provided important proof of concept that remyelination correlated with functional recovery in MS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. You, Y. et al. Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis. Neurol. Neuroimmunol. Neuroinflamm. 7, e700 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Chang, A., Tourtellotte, W. W., Rudick, R. & Trapp, B. D. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N. Engl. J. Med. 346, 165–173 (2002). This paper provided evidence that chronic lesions in MS are replete with premyelinating oligodendrocytes that seem to be stalled at the level of differentiation, a finding that has formed the basis for pro-differentiation approaches to remyelination.

    Article  PubMed  Google Scholar 

  46. Kuhlmann, T. et al. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 131, 1749–1758 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Duncan, I. D. et al. The adult oligodendrocyte can participate in remyelination. Proc. Natl Acad. Sci. USA 115, 11807–11816 (2018).

    Article  Google Scholar 

  48. Yeung, M. S. Y. et al. Dynamics of oligodendrocyte generation in multiple sclerosis. Nature 566, 538–542 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Samanta, J. et al. Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. Nature 526, 448–452 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zawadzka, M. et al. CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell 6, 578–590 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Wooliscroft, L. et al. Phase I randomized trial of liothyronine for remyelination in multiple sclerosis: a dose-ranging study with assessment of reliability of visual outcomes. Mult. Scler. Relat. Disord. 41, 102015 (2020).

    Article  PubMed  Google Scholar 

  52. Hartley, M. D. et al. Myelin repair stimulated by CNS-selective thyroid hormone action. JCI Insight 4, e126329 (2019).

    Article  PubMed Central  Google Scholar 

  53. Huang, J. K. et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat. Neurosci. 14, 45–53 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Brown, J. W. L. et al. Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study. Lancet Neurol. 20, 709–720 (2021).

    Article  CAS  PubMed  Google Scholar 

  55. El-Etr, M., Akwa, Y., Rame, M., Schumacher, M. & Sitruk-Ware, R. Nestorone, a 19nor-progesterone derivative boosts remyelination in an animal model of demyelination. CNS Neurosci. Ther. 27, 464–469 (2021).

    Article  CAS  PubMed  Google Scholar 

  56. Mi, S. et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat. Med. 13, 1228–1233 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Lu, C. et al. G-protein-coupled receptor Gpr17 regulates oligodendrocyte differentiation in response to lysolecithin-induced demyelination. Sci. Rep. 8, 4502 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Merten, N. et al. Repurposing HAMI3379 to block GPR17 and promote rodent and human oligodendrocyte differentiation. Cell Chem. Biol. 25, 775–786 e775 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Peppard, J. V. et al. High-content phenotypic screening and triaging strategy to identify small molecules driving oligodendrocyte progenitor cell differentiation. J. Biomol. Screen 20, 382–390 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Joubert, L. et al. Chemical inducers and transcriptional markers of oligodendrocyte differentiation. J. Neurosci. Res. 88, 2546–2557 (2010).

    CAS  PubMed  Google Scholar 

  61. Deshmukh, V. A. et al. A regenerative approach to the treatment of multiple sclerosis. Nature 502, 327–332 (2013). One of the earliest phenotypic screens for enhancing MBP+ oligodendrocytes from OPCs, this paper established many aspects of the now typical screening cascade.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mei, F. et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat. Med. 20, 954–960 (2014). This paper used micropillar plates as a novel phenotypic screening technology to measure ‘myelination’ in vitro and extensively characterized the pro-myelinating effects of clemastine.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lariosa-Willingham, K. D. et al. A high throughput drug screening assay to identify compounds that promote oligodendrocyte differentiation using acutely dissociated and purified oligodendrocyte precursor cells. BMC Res. Notes 9, 419 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Najm, F. J. et al. Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells. Nat. Biotechnol. 31, 426–433 (2013). The derivation and characterization of PSC-derived OPCs that retain the ability to differentiate to oligodendrocytes in vitro and in vivo is described in this paper.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Elitt, M. S. et al. Chemical screening identifies enhancers of mutant oligodendrocyte survival and unmasks a distinct pathological phase in pelizaeus–Merzbacher disease. Stem Cell Rep. 11, 711–726 (2018).

    Article  CAS  Google Scholar 

  66. Najm, F. J. et al. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature 522, 216–220 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hubler, Z. et al. Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination. Nature 560, 372–376 (2018). This paper reported inhibition of specific cholesterol pathway enzymes and accumulation of 8,9-unsaturated sterols as a unifying ‘off-target’ mechanism by which many small molecules identified in phenotypic screens promote oligodendrocyte formation and remyelination.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Guo, Y. E., Suo, N., Cui, X., Yuan, Q. & Xie, X. Vitamin C promotes oligodendrocytes generation and remyelination. Glia 66, 1302–1316 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Li, W. et al. High-throughput screening for myelination promoting compounds using human stem cell-derived oligodendrocyte progenitor cells identifies novel targets. Preprint at bioRxiv https://doi.org/10.1101/2022.01.18.476755 (2022).

  70. Redmond, S. A. et al. Somatodendritic expression of JAM2 inhibits oligodendrocyte myelination. Neuron 91, 824–836 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bechler, M. E., Byrne, L. & Ffrench-Constant, C. CNS myelin sheath lengths are an intrinsic property of oligodendrocytes. Curr. Biol. 25, 2411–2416 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wang, J. et al. Transcription factor induction of human oligodendrocyte progenitor fate and differentiation. Proc. Natl Acad. Sci. USA 111, 2885–2894 (2014).

    Google Scholar 

  73. Manousi, A. et al. Identification of novel myelin repair drugs by modulation of oligodendroglial differentiation competence. EBioMedicine 65, 103276 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Madhavan, M. et al. Induction of myelinating oligodendrocytes in human cortical spheroids. Nat. Methods 15, 700–706 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mei, F. et al. Identification of the κ-opioid receptor as a therapeutic target for oligodendrocyte remyelination. J. Neurosci. 36, 7925–7935 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gonzalez, G. A. et al. Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system. Sci. Rep. 6, 31599 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rankin, K. A. et al. Selective estrogen receptor modulators enhance CNS remyelination independent of estrogen receptors. J. Neurosci. 39, 2184–2194 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Chen, Y. et al. Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and remyelination. PLoS ONE 12, e0189380 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Jakel, S. et al. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 566, 543–547 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Korade, Z. et al. The effect of small molecules on sterol homeostasis: measuring 7-dehydrocholesterol in Dhcr7-deficient Neuro2a cells and human fibroblasts. J. Med. Chem. 59, 1102–1115 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Muller, C., Junker, J., Bracher, F. & Giera, M. A gas chromatography–mass spectrometry-based whole-cell screening assay for target identification in distal cholesterol biosynthesis. Nat. Protoc. 14, 2546–2570 (2019).

    Article  PubMed  Google Scholar 

  82. Byskov, A. G. et al. Chemical structure of sterols that activate oocyte meiosis. Nature 374, 559–562 (1995).

    Article  CAS  PubMed  Google Scholar 

  83. Pleshinger, M. J. et al. Inhibition of SC4MOL and HSD17B7 shifts cellular sterol composition and promotes oligodendrocyte formation. RSC Chem. Biol. 3, 56–68 (2022).

    Article  CAS  PubMed  Google Scholar 

  84. Hubler, Z. et al. Modulation of lanosterol synthase drives 24,25-epoxysterol synthesis and oligodendrocyte formation. Cell Chem. Biol. 28, 866–875 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sax, J. L., Hubler, Z., Allimuthu, D. & Adams, D. J. Screening reveals sterol derivatives with pro-differentiation, pro-survival, or potent cytotoxic effects on oligodendrocyte progenitor cells. ACS Chem. Biol. 16, 1288–1297 (2021).

    Article  CAS  PubMed  Google Scholar 

  86. Allimuthu, D. et al. Diverse chemical scaffolds enhance oligodendrocyte formation by inhibiting CYP51, TM7SF2, or EBP. Cell Chem. Biol. 26, 593–599 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sax, J. L. et al. Enhancers of human and rodent oligodendrocyte formation predominantly induce cholesterol precursor accumulation. ACS Chem. Biol. https://doi.org/10.1021/acschembio.2c00330 (2022).

  88. Martin, E. Teriflunomide promotes oligodendroglial 8,9-unsaturated sterol accumulation and CNS remyelination. Neurol. Neuroimmunol. Neuroinflamm. 8, e1091 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Berghoff, S. A., Spieth, L. & Saher, G. Local cholesterol metabolism orchestrates remyelination. Trends Neurosci. 45, 272–283 (2022). This recent review provides a broad perspective of multiple ways through which sterol synthesis, accumulation, and recycling contributes to myelin formation and remyelination.

    Article  CAS  PubMed  Google Scholar 

  90. Berghoff, S. A. et al. Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis. Nat. Neurosci. 24, 47–60 (2021).

    Article  CAS  PubMed  Google Scholar 

  91. Cantuti-Castelvetri, L. et al. Defective cholesterol clearance limits remyelination in the aged central nervous system. Science 359, 684–688 (2018).

    Article  CAS  PubMed  Google Scholar 

  92. Banik, N. L. & Davison, A. N. Exchange of sterols between myelin and other membranes of developing rat brain. Biochem. J. 122, 751–758 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Petersen, M. A. et al. Fibrinogen activates BMP signaling in oligodendrocyte progenitor cells and inhibits remyelination after vascular damage. Neuron 96, 1003–1012 e1007 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Segel, M. et al. Niche stiffness underlies the ageing of central nervous system progenitor cells. Nature 573, 130–134 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Neumann, B. et al. Metformin restores CNS remyelination capacity by rejuvenating aged stem cells. Cell Stem Cell 25, 473–485 e478 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rawji, K. S. et al. Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system. Acta Neuropathol. 139, 893–909 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Espinosa-Hoyos, D. et al. Engineered 3D-printed artificial axons. Sci. Rep. 8, 478 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Early, J. J. An automated high-resolution in vivo screen in zebrafish to identify chemical regulators of myelination. eLife 7, e35136 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Acimovic, J. & Rozman, D. Steroidal triterpenes of cholesterol synthesis. Molecules 18, 4002–4017 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank P. Tesar, S. Stubblefield, and members of the Adams Lab for critical feedback. Research in the Adams laboratory in the area covered by this Perspective was generously supported by the National Institute of Neurological Disorders and Stroke (NS115867), the Conrad N. Hilton, Edward Mallinckrodt, Jr., and G. Harold and Leila Y. Mathers Foundations, and the National MS Society (to D.J.A.).

Author information

Authors and Affiliations

  1. Convelo Therapeutics, Cleveland, OH, USA

    Andrew V. Caprariello

  2. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Drew J. Adams

Authors
  1. Andrew V. Caprariello
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Drew J. Adams
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Drew J. Adams.

Ethics declarations

Competing interests

The authors declare the following competing interests: D.J.A. is a founder, consultant, director, and shareholder of Convelo Therapeutics, which seeks to develop remyelinating therapeutics. D.J.A., is an inventor on patents and patent applications that have been licensed to Convelo. A.V.C. is an employee of Convelo Therapeutics. Convelo has not provided any support to the Adams Lab.

Peer review

Peer review information

Nature Chemical Biology thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Caprariello, A.V., Adams, D.J. The landscape of targets and lead molecules for remyelination. Nat Chem Biol 18, 925–933 (2022). https://doi.org/10.1038/s41589-022-01115-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41589-022-01115-2

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research