α-synuclein异常增加致BDNF轴突逆向运输受损的分子机制研究

In Parkinson’s disease (PD)，increasedα-synuclein causes degeneration of dopaminergic neurons, however, the underlying mechanism remains unclear. It is known that retrograde transported BDNF/TrkB signal is crucial for promoting the survival of dopaminergic neurons. Our previous study showed that increased α-synuclein induces significantly over-activated Rab5 and impaired BDNF retrograde transport. Since Rab5 is the key regulator of early endosomes carrying retrograde transported BDNF，our results suggested that dysregulation of Rab5 activity might play an important role in the process of degeneration of dopaminergic neurons caused by increased α-synuclein. Hence，we will further in this project: (1) observe whether manipulation of Rab5 activity would rescue BDNF retrograde transport deficits caused by increased α-synuclein; (2) screen the upstream regulators responsible for over-activated Rab5 induced by increased α-synuclein; (3) explore the mechanism underlying impaired BDNF retrograde transport caused by abnormal upstream regulators, which would result in the progression of PD. This project will help to replenish to the PD pathogenesis and provide new clues for the diagnosis and treatment of PD.

帕金森病（PD）中α-synuclein异常增加引起多巴胺能神经元变性死亡，但机制尚不明确。已知轴突逆向运输BDNF/TrkB信号为维持多巴胺能神经元存活所必需。我们的前期研究表明α-synuclein异常增加可致Rab5异常激活和BDNF轴突逆向运输受损，而Rab5是调控承载BDNF轴突逆向运输的早期内体的关键调节因子，提示Rab5活性失常是α-synuclein异常增加致多巴胺能神经元变性死亡的重要因素。据此，本课题将进一步：（1）观察调控Rab5活性是否改善α-syn异常增加引起的BDNF轴突逆向运输受损，（2）筛选异常增加的α-synuclein导致Rab5异常激活的上游调节因子，（3）明确上游调节因子异常对BDNF轴突逆向运输的影响、致PD发生的机制。课题的实施将完善PD发病机制的认识，为PD诊疗提供新的思路。

帕金森病（PD）中α-突触核蛋白（α-synuclein）异常增加引起多巴胺能神经元变性死亡，但机制尚不明确。我们的研究表明，α-synuclein与标记早期内体的Rab5有共定位，过量的α-synuclein引起Rab5活性异常增加，导致BDNF轴突逆向运输受损。下调Rab5活性可改善异常增加的α-synuclein引起的BDNF轴突逆向运输障碍、BDNF下游信号激活受阻、维持神经元的生长。Rin3是调控Rab5活性的上游调节因子，当敲低Rin3的表达水平，Rab5激活减少，可逆转因α-synuclein异常增加导致的BDNF轴突逆向运输受损。此外，我们进一步构建了老年男性外周血诱导的多能干细胞（SIAISi012-A），拟诱导分化为人的神经细胞，进一步验证上述实验结果。本课题通过BDNF 轴突逆向运输异常及 BDNF/TrkB 信号缺损解释帕金森病中神经元变性死亡的病理过程，通过 Rab 蛋白活性调控异常解释异常增加的 α-synuclein导致 BDNF 轴突逆向运输障碍的可能机制，帮助了解 α-synuclein影响神经元轴突运输的具体过程和分子机制，为帕金森病发病机制的探索、有效的诊疗提供新的线索。