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。和免疫性脱髓鞘不同，WML髓鞘脱失可能是轴突损害的继发结果。我们发现WML模型中，伴随着髓鞘脱失，神经元轴突结旁区线粒体存在异常堆积和结构异常，但二者的因果关系和机制不明。我们提出假说: 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。为验证假说，拟采用体外有髓背根神经培养和BCAS动物模型，通过分子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作用。本研究将从轴突内线粒体锚定影响脱髓鞘这一新视角展开研究，阐释WML病理机制。

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 increase 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: under WML condition, increased docking mitochondria in axonal paranode area is the early change of demyelination, and dysfunction of mitochondria may occur due to swollen and abnormal metablism over time. Then the abnormal mitochondria lead to a reduction in the number of Mitochondria-associated ER membrane(MAM). The acetylation state of Caspr is necessary for maintaining stability of Caspr and Contactin, sustaining stability of myline. Under WML condition, the reduction of MAM induced the activation of EndoH, which then increase deacetylation of Caspr by EndoH, eventually lead to dissociation of Caspr and Contactin and myelin instability. To test this hypothesis, we will use in vitro DRG cells culture and bilateral common carotid artery stenosis (BCAS) 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.