Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
GeNeuro, Chemin du Pré-Fleuri 3, Geneva, Switzerland.
Glia. 2019 Jan;67(1):160-170. doi: 10.1002/glia.23535. Epub 2018 Nov 14.
Remyelination in the adult CNS depends on activation, differentiation, and functional integration of resident oligodendroglial precursor cells (OPCs) and constitutes the only spontaneous neuroregenerative process able to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis. The proteins encoded by p57kip2- and by human endogenous retrovirus type W (pHERV-W) envelope genes were previously identified as negative regulators of OPC maturation. We here focused on the activity of the ENV protein and investigated how it can be neutralized for an improved myelin repair. We could demonstrate that myelination in vitro is severely affected by this protein but that application of an anti-ENV neutralizing antibody, currently investigated in clinical trials, can rescue the generation of internodes. We then compared p57kip2 and ENV dependent inhibitory mechanisms and found that a dominant negative version of the p57kip2 protein can equally save OPCs from myelination failure in response to ENV-mediated TLR4 activation. Additional experiments addressing p57kip2's underlying mode of action revealed a direct interaction with ATP6v1d, a central component of a vascular ATPase. Its pharmacological blocking was then shown to exert an analogous myelination rescue effect in presence of the ENV protein. Therefore, our study provides mechanistic insights into oligodendroglial inhibition processes and presents three different means to counteract the anti-myelination effect of the ENV protein. These observations are therefore of interest in light of understanding the complexity of the numerous oligodendroglial inhibitors and might promote the establishment of novel regenerative therapies.
成年中枢神经系统中的髓鞘再生依赖于固有少突胶质前体细胞（OPC）的激活、分化和功能整合，并且是唯一能够在少突胶质细胞和髓鞘丧失时补偿功能缺陷的自发神经再生过程，如多发性硬化症中所见。先前已经鉴定出 p57kip2 和人类内源性逆转录病毒 W 型（pHERV-W）包膜基因编码的蛋白是 OPC 成熟的负调控因子。我们在这里重点研究了 ENV 蛋白的活性，并研究了如何中和它以改善髓鞘修复。我们可以证明，体外髓鞘形成受到该蛋白的严重影响，但应用目前正在临床试验中研究的抗 ENV 中和抗体可以挽救节间的生成。然后，我们比较了 p57kip2 和 ENV 依赖的抑制机制，发现 p57kip2 蛋白的显性负突变体同样可以挽救 OPC 免受 ENV 介导的 TLR4 激活引起的髓鞘形成失败。解决 p57kip2 潜在作用机制的额外实验表明，它与血管 ATP 酶中心组成部分 ATP6v1d 直接相互作用。然后证明其药理学阻断在存在 ENV 蛋白的情况下发挥类似的髓鞘修复作用。因此，我们的研究为少突胶质抑制过程提供了机制见解，并提出了三种不同的方法来对抗 ENV 蛋白的抗髓鞘作用。这些观察结果对于理解众多少突胶质抑制剂的复杂性很有意义，并可能促进新的再生治疗方法的建立。
