少突胶质细胞特异性蛋白Ermin通过细胞骨架调控中枢神经系统脱髓鞘病变和髓鞘再生

Homeostasis imbalance of the myelin sheath is among the key mechanisms underlying aging of the nervous system. Oligodendrocytes (OLs) are myelin-forming cells in the central nervous system (CNS). The machineries responsible for the differentiation of OLs and the maintenance of myelin homeostasis remain largely uncharacterized. We found in the pilot study that depletion of Ermin, an OL-specific protein, failed to affect de novo myelin formation; however, aged mice deficient in Ermin displayed remarkably impaired architecture of myelin sheath and accelerated process of toxication-induced demyelination, suggesting that Ermin plays an essential regulatory role in the maintenance of myelin homeostasis. Our further accomplished investigations led to a hypothesis that Ermin interacts with the cytoskeleton regulator p116RIP to repress RhoA/Rac signaling in OL differentiation, and that Ermin expression is controlled by the upstream Hedgehog pathway. Thus, Ermin dysfunction may cause disturbed physiological remyelination and contribute to the pathogenesis of demyelinating disorders. In the present study, we will integrate cellular and molecular biology methods with electrophysiological and behavioral approaches in the analysis of cultured OLs, genetically modified mice and clinical specimens, aiming to dissect a detailed role of Ermin in maintaining the homeostasis of CNS myelin sheath. The anticipated findings hold out promise for the disclosure of novel mechanisms underlying demyelinating disorders and for the identification of new candidate targets in treating neurodegenerative diseases.

髓鞘失稳态是神经系统衰老的重要机制。少突胶质细胞（OL）是中枢神经系统的髓鞘形成细胞，但OL分化和髓鞘稳态维持的机制尚不完全清楚。我们前期研究发现，OL特异性蛋白Ermin缺陷小鼠虽然髓鞘发育正常，但在老龄鼠呈现显著的髓鞘结构紊乱和脱髓鞘病变，提示其是维持髓鞘稳态的关键分子。在已获得的研究线索基础上，我们提出Ermin通过与细胞骨架调控蛋白p116RIP相互作用，抑制下游RhoA/Rac通路，促进OL分化，而Ermin的表达受到Hedgehog信号调控；Ermin功能性缺失引起髓鞘再生障碍，并加速髓鞘脱失。本项目拟在培养细胞、基因敲除动物和临床标本等水平上，综合应用细胞与分子生物学、电生理和行为学方法，探讨Ermin在髓鞘稳态调控中的作用及其分子机制，以期为阐明脱髓鞘疾病的新机制和鉴定神经退行性疾病干预的新靶点提供实验依据。

髓鞘是包裹在有髓神经轴突外的细胞膜结构，对于神经兴奋沿神经纤维快速和定向传导，以及神经元轴突的营养和支持至关重要。髓鞘稳态失衡导致的髓鞘结构破坏和脱失是临床上常见的神经退行性病变，目前脱髓鞘以及髓鞘再生的机制还不完全清楚。本项目以中枢神经系统的髓鞘形成细胞—少突胶质细胞（OL）为研究对象，按照既定计划开展研究，探讨了其中特异表达的细胞骨架相关蛋白Ermin的功能，发现：1）Ermn基因缺失可导致较大月龄小鼠髓鞘超微结构出现异常，视神经电传导速度和运动协调能力下降；2）Ermn基因缺失能够加速中枢神经系统髓鞘损伤的进程，加重小鼠的脱髓鞘病变和行为学异常；3）Ermin促进COS-7和OLN-93细胞突起的生长，但是缺乏C端结构域的Ermin蛋白仍然能够促进OLN-93细胞突起和高级分支的形成；4）筛选出与Ermin相互作用蛋白Mprip/p116并证实二者之间能够直接相互作用；5）Ermin能够增强Mprip蛋白的稳定性；6）Ermin/Mprip能够通过抑制少突胶质细胞中RhoA的活性，促进少突胶质细胞突起的形成。本研究阐明了少突胶质细胞特异性蛋白Ermin在少突胶质细胞分化和脱髓鞘病理进程中的作用，从而为认识髓鞘功能障碍的新机制和鉴定神经退行性疾病干预的新靶点提供了新的思路。在本项目经费资助下，我们以项目负责人为通讯作者在Glia、Physiology & Behavior等杂志发表SCI论文2篇。