Disruption of Sema3A/Plexin-A1 inhibitory signalling in oligodendrocytes as a therapeutic strategy to promote remyelination
Disruption of Sema3A/Plexin-A1 inhibitory signalling in oligodendrocytes as a therapeutic strategy to promote remyelination
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DOI：
10.15252/emmm.201910378
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发表时间：
2019-09-30
影响因子：
11.1
通讯作者：
Bagnard, Dominique
中科院分区：
文献类型：
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作者：
Biname, Fabien;Pham-Van, Lucas D.;Bagnard, Dominique
目前多发性硬化症(MS)的治疗方法是调节疾病的炎症成分，但目前还没有修复病变的药物。我们的研究发现，在MS患者中，少突胶质细胞抑制剂Semaphorin 3A的信号受体Plexin-A1过度表达。使用一种新型的多肽拮抗剂，我们显示了在体外拮抗丛状蛋白A1时，Sema3A对少突胶质细胞迁移和分化的抑制作用的可能性。DTI-MRI显示了该化合物在体内的髓鞘保护作用，并在组织学水平上证实了该化合物在诱导脱髓鞘/再髓鞘小鼠模型中的作用。这种效应与长期治疗的动物完全保留下来的运动能力有关。给予多肽也显示了保护作用，导致在实验性自身免疫性脑炎(EAE)的背景下脱髓鞘的严重程度减轻。因此，抑制微环境分子屏障的破坏允许正常的髓鞘细胞发挥其自发的再髓鞘能力。这为患有一种尚无治疗选择的疾病的患者打开了前所未有的治疗机会。
Current treatments in multiple sclerosis (MS) are modulating the inflammatory component of the disease, but no drugs are currently available to repair lesions. Our study identifies in MS patients the overexpression of Plexin-A1, the signalling receptor of the oligodendrocyte inhibitor Semaphorin 3A. Using a novel type of peptidic antagonist, we showed the possibility to counteract the Sema3A inhibitory effect on oligodendrocyte migration and differentiation in vitro when antagonizing Plexin-A1. The use of this compound in vivo demonstrated a myelin protective effect as shown with DTI-MRI and confirmed at the histological level in the mouse cuprizone model of induced demyelination/remyelination. This effect correlated with locomotor performances fully preserved in chronically treated animals. The administration of the peptide also showed protective effects, leading to a reduced severity of demyelination in the context of experimental autoimmune encephalitis (EAE). Hence, the disruption of the inhibitory microenvironmental molecular barriers allows normal myelinating cells to exert their spontaneous remyelinating capacity. This opens unprecedented therapeutic opportunity for patients suffering a disease for which no curative options are yet available.