抑制mTOR通路对调节铁沉积和保护多巴胺神经元的机制研究

Parkinson's disease (PD) is the second most common neurodegenerative disease, and more and more evidence reveals that iron deposition and α-synuclein accumulation contribute to the dopaminergic neuron loss. Reducing the iron overload and promoting the clearance of α-synuclein have been suggested to be a therapeutic strategy for PD. It is reported that autophagy is not only a major pathway to clear α-synuclein but also involved in the iron metabolism. However, as the major pathway of autophagy, the roles of inhibiting mTOR pathway in regulating iron deposition and protecting dopaminergic neurons are not clear. We hypothesis that inhibiting mTOR pathway regulates the iron deposition and promotes the clearance of α-synuclein, which will protect the dopaminergic neurons. In this project, we will investigate the mechanism of regulating iron deposition and protecting dopaminergic neurons via inhibiting mTOR pathway in the PD mice model and iron overload cell model, which will provide the evidence of autophagy regulating iron metabolism. Also, we will employ corynoxine, which is a new mTOR inhibitor, to identify the important regulators of iron metabolism in the PD mice model and iron overload cell model, which will provide new thoughts and new directions to develop drugs for PD treatment.

黑质铁沉积和α-突触核蛋白聚集可诱导多巴胺神经元的丢失，从而引发帕金森病（PD）。减少铁沉积和清除α-突触核蛋白可能是治疗PD的有效策略。自噬不但是清除α-突触核蛋白的主要途径，自噬还参与细胞内铁代谢。抑制mTOR通路是诱导自噬的主要方式之一。我们推测，抑制mTOR通路可以调节铁代谢减少黑质铁沉积和促进α-突触核蛋白的清除，从而保护黑质多巴胺神经元。在本研究中，我们拟利用PD大鼠模型和高铁细胞模型研究mTOR通路对铁沉积、α-突触核蛋白聚集和多巴胺神经元死亡的调节作用，同时利用新型mTOR抑制剂—柯诺辛对PD铁沉积进行干预，为寻找抑制mTOR通路中重要的铁代谢调控因子，开发预防或治疗PD的新型药物提供新思路。

黑质铁沉积和α-突触核蛋白聚集可诱导多巴胺能神经元的丢失，从而引发帕金森病（PD），因此，减少黑质铁沉积和清除α-突触核蛋白可能是治疗PD的有效策略。自噬不但是清除α-突触核蛋白的主要途径，还参与细胞内铁代谢。抑制mTOR通路是诱导自噬的主要方式之一。在本课题中，我们采用鱼藤酮分别构建了PD急性毒性模型和慢性毒性模型，并利用新型mTOR抑制剂—柯诺辛进行干预。研究结果表明，抑制mTOR通路诱导自噬，可促进α-突触核蛋白的清除而减少其异常聚集，并通过抑制小胶质细胞激活而减少神经炎症，进而保护PD黑质区多巴胺能神经元，但是鱼藤酮诱导的黑质区铁染色阳性细胞数增加却没有明显改善。溶酶体是重要的储铁细胞器，研究报道TFEB可调节溶酶体再生，而抑制mTOR通路可激活TFEB。在本课题中我们观察到，高表达TFEB可促进溶酶体再生，增加不稳定Fe2+的储存，减少胞浆内的游离Fe2+，进而在PD黑质铁沉积诱发的多巴胺能神经元退变中发挥保护作用。以上研究结果为阐明mTOR通路保护多巴胺能神经元提供了新的理论基础，并为PD的预防或治疗研究提供了新思路。