神经元轴突内线粒体锚定在脑白质损害髓鞘稳定性障碍中的机制研究

The major pathological changes of cerebral white matter lesions (WML) induced by small vascular disease and chronic hypoperfusion is demyelination. Different with autoimmune demyelination, The WML demyelination might be the secondary change to axonal damage. Our previous study showed that chronic hypoperfusion can decrease axonal mitochondrial docking accompanied with demyelination, however the causal relationship between the two phenomena and the underlying molecular mechanism need to be further studied. Therefore, we put forward the hypothesis, axonal docking mitochondria may deacetylize Protein 4.1B which localized in axonal plasm through deacetylase Sirt3. The deacetylation state of Protein4.1B is necessary for maintaining stability of myelin. Under WML condition, the reduction of axonal mitochondrial docking decreased the deacetylation of Protein4.1B by Sirt 3,eventually lead to myelin instability. To test this hypothesis, we will use in vitro neuron and oligodendrocyte co-culture system and bilateral common carotid artery stenosis animal model. By molecular modulation of mitochondria docking proteins, we will investigate the important role of axonal docking mitochondria in maintenance of myelin stability. From the novel point of view that axonal mitochondria may regulate myelin stability, we will study the mechanism of WML induced demyelination. This will help us interpret the neural function defect caused by the WML and provide a new sight for clinical intervention.

脑小血管病及慢性颅内低灌注所致的脱髓鞘是脑白质损伤（WML）的主要病理改变。WML脱髓鞘和免疫性脱髓鞘机制不同。其髓鞘脱失可能是轴突损害的继发结果。我们的研究显示在WML模型中，伴随着髓鞘脱失，神经元轴突内线粒体存在锚定障碍。然而二者的因果关系和分子机制还有待确定。为此，我们提出假说：线粒体可能通过去乙酰化酶Sirt3使神经元微管蛋白Protein 4.1B去乙酰化，这种去乙酰化状态是髓鞘结构稳定所必须的；而在WML情况下，轴突内线粒体锚定障碍，降低了Sirt3对Protein4.1B的去乙酰化作用，最终导致髓鞘结构松散。为验证这一假说，我们将利用体外神经元少突胶质细胞共培养体系和WML动物模型，通过分子生物学手段干预线粒体锚定蛋白。探讨线粒体锚定在维持髓鞘结构稳定性中的重要作用。本研究将从神经元轴突内线粒体影响髓鞘结构这一新视角展开WML脱髓鞘机制的研究，对阐释WML病理机制有重要意义。

脑小血管病及慢性颅内低灌注所致的脱髓鞘是脑白质损伤（WML）的主要病理改变。WML 脱髓鞘和免疫性脱髓鞘机制不同。其髓鞘脱失可能是轴突损害的继发结果。我们的研究显示在WML 模型中，伴随着髓鞘脱失，神经元轴突内线粒体存在锚定障碍。然而二者的因果关系和分子机制还有待确定。为此，我们认为假说：线粒体可能通过去乙酰化酶Sirt3使神经元微管蛋白Protein 4.1B 去乙酰化，这种去乙酰化状态是髓鞘结构稳定所必须的；而在WML 情况下，轴突内线粒体锚定障碍，降低了Sirt3 对Protein4.1B 的去乙酰化作用，最终导致髓鞘结构松散。慢性低灌注状态下，神经元轴突内线粒体轴浆流发生异常，线粒体异常锚定增多。郎飞氏结结旁区堆积的线粒体功能障碍将导致线粒体-内质网桥接减少，进而导致内质网功能障碍。分布于内质网的糖苷酶Endo H进而被激活，介导Caspr蛋白质N端脱糖基化，引起结旁区髓鞘稳定复合物Capsr和Contactin相互黏附作用下降，继而出现血管性脱髓鞘现象。

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