基于转录因子TFEB调控自噬溶酶体通路研究异鼠李素治疗帕金森病的疗效与分子机制

帕金森病（PD）是一种由中脑多巴胺神经元逐渐缺失引发的常见的运动障碍疾病。最新研究证明了α-突触核蛋白（α-syn）聚集及NLRP3炎性小体在多巴胺神经元死亡和慢性小胶质细胞神经炎症中的关键作用。转录因子EB（TFEB）是调控自噬-溶酶体通路（ALP）的关键分子，激活TFEB可促进α-syn的降解，对PD具有治疗潜力。在初期研究中，我们从中药银杏的黄酮类成分中鉴定了异鼠李素为一个强效的TFEB激活剂，异鼠李素可增强ALP，促进α-syn降解，在PD的MPTP模型中具有保护作用。本项目将解析异鼠李素激活TFEB的分子机制，并验证异鼠李素通过促进α-syn和NLRP3炎性小体的自噬降解来保护多巴胺神经元、抑制小胶质细胞神经炎症的科学假说。我们的结果将首次证明TFEB激活是否能够同时清除PD中的α-syn和NLRP3炎性小体，并推进异鼠李素作为先导化合物用于以TFEB为靶点的PD新药开发。

Parkinson’s disease is a movement disorder caused by progressive loss of dopaminergic neurons in the midbrain. The most recent studies have proved the key roles of α-synuclein (α-syn) aggregation and NLRP3 inflammasomes in dopaminergic neuronal death and chronic microglial neuroinflammation. Activating the transcription factor EB (TFEB), a master regulator of autophagy-lysosomal pathway (ALP), has been shown promising for treating PD, mainly acting by promoting the degradation of α-syn. In our pilot study, isorhamnetin, a flavonoid isolated from the Chinese medicine Ginkgo biloba, was identified as a potent TFEB activator, which enhanced ALP, promoted α-syn degradation and showed protective effects in the MPTP model of PD. In this project, we will dissect the molecular mechanisms by which isorhamnetin activates TFEB, and validate the hypothesis that isorhamnetin may protect dopaminergic neurons and inhibit microglial neuroinflammation by promoting the autophagic degradation of α-syn and NLRP3 inflammasomes. Our results will prove for the first time whether TFEB activation clears bothα-syn and NLRP3 inflammasomes in PD and suggest isorhamnetin as a lead compound for TFEB-targeted anti-PD drugs development.