Rescuing the negative impact of human endogenous retrovirus envelope protein on oligodendroglial differentiation and myelination
Rescuing the negative impact of human endogenous retrovirus envelope protein on oligodendroglial differentiation and myelination
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DOI：
10.1002/glia.23535
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发表时间：
2019-01-01
期刊：
影响因子：
6.2
通讯作者：
Kuery, Patrick
中科院分区：
文献类型：
--
作者：
Goettle, Peter;Foerster, Moritz;Kuery, Patrick
成年CNS中的再髓鞘化依赖于驻留的少突胶质前体细胞（OPC）的活化、分化和功能整合，并且构成能够补偿在少突胶质细胞和髓鞘丧失时的功能缺陷的唯一自发神经再生过程，如在多发性硬化中观察到的。由p57 kip 2和人内源性逆转录病毒W型（pHERV-W）包膜基因编码的蛋白质先前被鉴定为OPC成熟的负调节因子。我们在这里专注于ENV蛋白的活性，并研究如何中和它以改善髓鞘修复。我们可以证明，在体外髓鞘形成受到这种蛋白质的严重影响，但目前在临床试验中研究的抗ENV中和抗体的应用，可以挽救节间的产生。然后，我们比较了p57 kip 2和ENV依赖的抑制机制，发现p57 kip 2蛋白的显性负性版本同样可以响应ENV介导的TLR 4激活而使OPCs免于髓鞘形成失败。进一步的实验表明p57 kip 2的潜在作用模式与血管ATP酶的核心成分ATP 6v 1d直接相互作用。其药理学阻断随后显示在ENV蛋白存在下发挥类似的髓鞘形成拯救作用。因此，我们的研究提供了机制的见解少突胶质细胞抑制过程，并提出了三种不同的手段来抵消抗髓鞘形成的ENV蛋白的效果。因此，这些观察结果在了解许多少突胶质细胞抑制剂的复杂性方面是有意义的，并可能促进新的再生疗法的建立。
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.