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

机译：8,9-不饱和固醇的积累驱动少突胶质细胞形成和髓鞘再生

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摘要

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(1-3). 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 vivo(4-10). 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.
机译：髓鞘的再生由少突胶质祖细胞介导，少突胶质祖细胞是中枢神经系统（CNS）中大量干细胞的种群，是新的有髓突少突胶质细胞的主要来源。中枢神经系统中产生髓磷脂的少突胶质细胞的丢失是许多神经系统疾病的基础，包括多发性硬化症和多种遗传疾病（1-3）。高通量化学筛选方法已被用于鉴定刺激少突胶质祖细胞形成少突胶质细胞并在体内功能上增强髓鞘再生的小分子（4-10）。在这里，我们表明，这些促髓鞘形成的小分子的作用范围广泛，不是通过其经典靶标而是通过直接抑制CYP51，TM7SF2或EBP（胆固醇生物合成途径中的一小部分酶）来实现。这些酶的8,9-不饱和甾醇底物的后续积累是促进少突胶质细胞形成的关键机理，因为当以纯化形式提供给少突胶质祖细胞时，8,9-不饱和固醇是有效的，而缺乏这种结构特征的类似固醇没有效果。总的来说，我们的结果为大多数已知的少突胶质细胞形成小分子增强剂定义了一种基于甾醇的统一作用机制，并突出了特定靶标以推动最佳髓鞘再生疗法的发展。

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  • 来源
    《Nature》 |2018年第7718期|372-376|共5页
  • 作者

    Hubler Zita; Allimuthu Dharmaraja; Bederman Ilya; Elitt Matthew S.; Madhavan Mayur; Allan Kevin C.; Shick H. Elizabeth; Garrison Eric; Karl Molly T.; Factor Daniel C.; Nevin Zachary S.; Sax Joel L.; Thompson Matthew A.; Fedorov Yuriy; Jin Jing; Wilson William K.; Giera Martin; Bracher Franz; Miller Robert H.; Tesar Paul J.; Adams Drew J.;

  • 作者单位

    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Sch Med, Dept Pediat, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA;

    George Washington Univ, Sch Med & Hlth Sci, Dept Anat & Regenerat Biol, Washington, DC 20052 USA;

    George Washington Univ, Sch Med & Hlth Sci, Dept Anat & Regenerat Biol, Washington, DC 20052 USA;

    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Sch Med, Small Mol Drug Dev Core, Cleveland, OH USA;

    Rice Univ, Dept Biosci, Houston, TX USA;

    Rice Univ, Dept Biosci, Houston, TX USA;

    Leiden Univ, Med Ctr, Ctr Prote & Metabol, Leiden, Netherlands;

    Ludwig Maximilians Univ Munchen, Ctr Drug Res, Dept Pharm, Munich, Germany;

    George Washington Univ, Sch Med & Hlth Sci, Dept Anat & Regenerat Biol, Washington, DC 20052 USA;

    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA;

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