Parkin在血管性认知功能障碍中介导神经元突触损伤的机制研究

Research shows that cerebral small vessel disease may result in vascular cognitive impairment, but its mechanism still not clear. Our preliminary studies demonstrated that: Parkin play an important role in cerebral chronic low perfusion caused vascular cognitive impairments, the mechanism may be related to the involvement of Parkin in the adjustment of prefrontal synaptic function and plasticity. In neurons, we hypothesized that chronic low hypoxia and low glucose could decrease Parkin expression, Then Parkin induced Siah ubiquitination and protein degradation is reduced, and the high expressed Siah further accelerated the degradation of synaptic protein Syp. On the other hand, In the astrocytes and neurons co-culture system, we observed that Parkin expressed in astrocytes also plays an important regulatory role on neurons synapse number and functions. This study will mainly application of molecular biological and electrophysiology technique, discusses under the cerebral chronic low perfusion state, the molecular mechanism of astrocyte Parkin indirect influence synaptic function of neurons. The Parkin-KO mice will be further used to make vascular dementia model, to further verify the effect of Parkin on the regulation of vascular cognitive impairment. This study is important to elucidate the mechanisms of vascular cognitive impairment, And we hope it will provide a new idea for the treatment of cognitive dysfunction.

研究证明，脑小血管病可导致血管性认知功能障碍，但其机制不清。我们的前期研究提示：Parkin可能在慢性低灌注导致的血管性认知功能障碍中扮演了重要角色，其机制可能与其参与了前额叶突触功能和可塑性有关。在神经元中，我们推测慢性低糖低氧导致的Parkin表达下降，可能促使Siah的泛素化和蛋白降解减少，而高表达的Siah进一步加速了神经元突触蛋白Syp的降解。然而在胶质细胞与神经元共培养的体系中，我们观察到星形胶质细胞中的Parkin竟然也对神经元突触数目及功能起到重要的调节作用。本研究将主要应用分子生物学和电生理技术，着重探讨在慢性低灌注状态下，胶质细胞中Parkin间接影响神经元的突触功能的分子机制。在动物实验中将进一步验证Parkin对血管性认知功能障碍动物模型认知水平和电生理的调节作用。对阐明血管性认知功能障碍的机制有重要意义，将为认知功能障的治疗提供新的思路。

研究证明脑小血管病可导致血管性认知功能障碍，但其机制不清。神经元在慢性低灌注导致的血管性认知功能障碍中扮演了重要角色，参与了前额叶突触功能和可塑性有关。在神经元中，慢性低糖低氧导致Parkin表达下降，促使Siah的泛素化和蛋白降解减少，而高表达的Siah进一步加速了神经元突触蛋白Syp的降解。低糖低氧刺激导致神经元内线粒体运动减少，锚定增加，进而影响脱髓鞘。在胶质细胞与神经元共培养的体系中，我们观察到不同氧糖条件下星形胶质细胞中的HIF竟然对神经元具有不同的调节功能。本研究着重探讨在慢性低灌注状态下，直接或间接影响神经元的突触功能的分子机制，对阐明血管性认知功能障碍的机制有重要意义，将为认知功能障的治疗提供新的思路。