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

项目名称： 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

项目编号： No.81471173

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 崔梅

作者单位： 复旦大学

项目金额： 70万元

中文摘要： 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。

中文关键词： 脑白质损害；脱髓鞘；线粒体锚定；线粒体Sirt；3；Protein；4.1B

英文摘要： 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.

英文关键词： white matter lesions;demyelination;mitochondrial docking;mitochondrial sirt3;protein 4.1B