基于自噬溶酶体通路研究一种小分子化合物用于治疗帕金森氏病的实验研究

Parkinson’s disease (PD) is the second most common neurodegenerative disorder without curable drugs. Autophagy-lysosome pathway dysfunction has been implicated in the pathogenesis of PD and activation of autophagy-lysosome pathway is regarded as a promising strategy for PD treatment. Recently, transcription factor EB (TFEB) was identified as a master regulator of autophagy and lysosomal biogenesis. Increasing evidence has demonstrated that genetic or pharmacological activation of TFEB ameliorates neurotoxicity and rescues neurodegenerative phenotypes in PD animal models, suggesting that small molecules activate of TFEB is effective for treating PD. However, TFEB activators are rarely identified. Thus, discovery of novel TFEB activator and investigate its neuroprotective effects in PD cells and animal models are urgently needed. Our preliminary data shows that a novel synthesized compound E4 activates TFEB to enhance autophagy and lysosomal biogenesis via inhibition of mTOR. In addition, E4 protects MPP+-induced cell injury and promotes the degradation of α-synuclein. Based on these promising data, we propose that E4 is a novel TFEB activator and is promising for the treatment of PD. The present project aims to delineate how E4 activates TFEB and examine the neuroprotective of E4 in PD cell and animal models. Our studies will provide important information for further development of E4 as a novel TFEB activator for the disease-modifying treatment of PD.

帕金森氏病(PD)是全球第二大神经退行性疾病，然而目前尚无有效的治疗药物，因此开发新型的PD治疗药物具有重要的意义。自噬溶酶体通路的失调在PD的发生和发展中具有重要作用，激活自噬有望成为治疗PD的有效方式。转录因子EB (TFEB)是调控自噬和溶酶体生物合成的关键蛋白，通过激活TFEB进而促进自噬和溶酶体生物合成的小分子化合物有望开发成治疗PD的新型药物。我们的前期合成一种小分子化合E4，并发现其能激活TFEB并增强自噬与溶酶体生物合成，进一步结果显示E4能够在细胞水平上减少MPP+导致的细胞损伤并能清楚α-突触核蛋白。因此，E4是一种TFEB的新型激活剂，对PD可能具有潜在的治疗效果。本课题将研究E4激活TFEB的分子机制并评价E4在PD细胞及动物模型中的神经保护作用，从而为开发新型TFEB激活剂治疗PD提供重要信息。

帕金森氏病 (Parkinson’s disease, PD) 是以运动功能障碍为主要临床特征，全球第二大神经退行性疾病。我国65 岁以上人群中约有1.7％的PD 患者。然而该疾病尚未有特效的治疗药物。因此寻找新型的治疗药物具有重要的意义。近年来研究表明激活转录因子EB介导的自噬溶酶体通路的小分子化合物有望成为治疗PD的有效候选药物。该项目主要研究一种小分子化合物通过激活自噬对对PD的保护作用。该项目研究发下小分子化合物E4能够有效激活TFEB介导的自噬和溶酶的生物合成，其作用机制是通过抑制mTOR信号通路。同时该化合物在PD细胞和动物模型上具有神经保护作用，提示该小分子化合物有望进一步开发成为治疗PD的候选药物。

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