内源性大麻素通过Ermin调控少突胶质细胞分化及其在髓鞘病变中的作用

Myelination deficits and demyelination are critical nervous disorders. Endocannabinoids (eCBs), upon engagement with the specific receptor, CB1R, play pivotal roles in oligodendrocyte differentiation, myelination and myelin regeneration, the underlying mechanisms of which remain largely elusive. We found previously that the ERM (ezrin/radixin/moesin) family protein Ermin, which was expressed exclusively in oligodendrocytes, is a key mediator of myelination. In addition, concurrent eCB and Ermin downregulation was observed in a mouse model of demyelination. Based on the data obtained from our pilot experiments, we propose that eCBs switch on the expression of Ermin via protein kinase A (PKA) and Sp1 signaling in differentiating oligodendrocytes; Ermin facilitates cytoskeleton reorganization by bridging Tubulins and the myelin basic protein (MBP), while Ermin association with A kinase anchoring protein 2 (AKAP2) helps localize PKA on the cytoskeleton, enabling its extensive participation in oligodendrocyte morphogenesis and migration required for myelination. This study attempts to dissect the precise machinery of myelination mediated by eCBs and the downstream effector, Ermin, using the established CB1R conditional knockout and Ermin-deficient mouse models, which will hopefully lead to a clearer understanding of the regulatory role of eCBs in oligodendrocyte differentiation and myelin formation, and thereby provide rationale for potential targeted intervention of clinical myelin disorders.

髓鞘形成障碍和脱髓鞘疾病是严重的神经系统疾病，内源性大麻素（eCB）通过其受体CB1R促进少突胶质细胞（OL）的分化和髓鞘的发育与再生，但具体机制并不清楚。我们发现，OL中特异表达的Ermin蛋白介导上述过程，eCB和Ermin在脱髓鞘动物模型中显著下调。结合前期研究结果我们提出，eCB通过蛋白激酶A（PKA）/Sp1通路上调Ermin，后者通过连接微管蛋白和髓鞘碱性蛋白（MBP）参与细胞骨架的重组，并借助A型激酶锚定蛋白2反馈促进PKA结合于细胞骨架，从而调控OL分化中细胞形态的改变和髓鞘形成中细胞的迁移。本项目在前期成功建立CB1R条件性剔除和Ermin缺陷小鼠的基础上，深入探讨eCB诱导Ermin表达以及Ermin促进髓鞘形成的分子机制，以期阐明eCB调控OL分化和髓鞘功能的基本途径，并为髓鞘相关疾病的靶向干预提供理论依据。

髓鞘形成障碍和脱髓鞘疾病是严重的神经系统疾病，内源性大麻素（eCB）通过其受体CB1R促进少突胶质细胞（OL）的分化和髓鞘的发育与再生，但具体机制并不清楚。我们发现，OL中特异表达的Ermin蛋白介导上述过程，eCB和Ermin在脱髓鞘动物模型中显著下调。在这些研究结果以及前期成功建立的CB1R条件性剔除和Ermin缺陷小鼠的基础上，本研究综合应用电生理、行为学和分子生物学等方法，探讨了Ermin在少突胶质细胞分化、髓鞘形成和再生障碍中的作用，并取得了以下主要研究结果：1. Ermin的表达与髓鞘发育的时间基本一致，且在小鼠老龄期与髓鞘结构的维持有密切关系； 2. Ermin敲除能够影响年龄较大小鼠的运动能力，神经电传导速度减慢，在脱髓鞘疾病模型中加重髓鞘的破坏程度和小鼠的运动障碍；3. Ermin能够促进少突胶质细胞突起形成，参与髓鞘的维持以及损伤后的再生，并且不影响髓鞘发育过程；4. 在进一步的神经机制研究中发现，Ermin通过Mprip/p116RIP介导的RhoA活性调节促进少突胶质细胞骨架重组。上述研究为认识髓鞘结构维持和髓鞘再生的调控机制提供了新思路，并为通过靶向eCB/Ermin抑制脱髓鞘疾病的进展提供了重要依据。

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