Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination.
Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination.
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DOI：
10.1038/s41586-018-0360-3
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发表时间：
2018-08
期刊：
影响因子：
64.8
通讯作者：
Adams DJ
中科院分区：
文献类型：
--
作者：
Hubler Z;Allimuthu D;Bederman I;Elitt MS;Madhavan M;Allan KC;Shick HE;Garrison E;T Karl M;Factor DC;Nevin ZS;Sax JL;Thompson MA;Fedorov Y;Jin J;Wilson WK;Giera M;Bracher F;Miller RH;Tesar PJ;Adams DJ
髓鞘的再生是由少突胶质前体细胞(OPC)介导的，OPC是中枢神经系统中丰富的干细胞群体，也是新的髓鞘少突胶质细胞的主要来源。中枢神经系统(CNS)中产生髓鞘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(MS)和各种遗传性疾病。利用高通量化学筛选方法，我们和其他人已经确定了刺激OPC形成少突胶质细胞并在功能上促进体内再髓鞘形成的小分子。在这里，我们展示了广泛的这些亲髓鞘小分子的功能，不是通过它们的典型靶标，而是通过直接抑制细胞色素P450(细胞色素P450，51家族)、TM7SF2或EBP(胆固醇生物合成途径中的一系列酶)来发挥作用。随后这些酶的8，9-不饱和类固醇底物的积累是促进少突胶质细胞形成的关键机制节点，因为8，9-不饱和类固醇在以纯化形式提供给OPC时是有效的，而缺乏这种结构特征的类似类固醇则没有作用。总而言之，我们的结果为大多数已知的少突胶质细胞形成的小分子增强剂定义了一个统一的基于类固醇的作用机制，并突出了推动最佳再髓鞘疗法发展的特定靶点。
Regeneration of myelin is mediated by oligodendrocyte progenitor cells (OPCs), an abundant stem cell population in the CNS and the principal source of new myelinating oligodendrocytes. Loss of myelin-producing oligodendrocytes in the central nervous system (CNS) underlies a number of neurological diseases, including multiple sclerosis (MS) and diverse genetic diseases. Using high throughput chemical screening approaches, we and others have identified small molecules that stimulate oligodendrocyte formation from OPCs and functionally enhance remyelination in vivo. Here we show a broad range of these pro-myelinating small molecules function not through their canonical targets but by directly inhibiting CYP51 (cytochrome P450, family 51), TM7SF2, or EBP (emopamil binding protein), 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 OPCs in purified form while analogous sterols lacking 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.