Dynasore Suppresses mTORC1 Activity and Induces Autophagy to Regulate the Clearance of Protein Aggregates in Neurodegenerative Diseases
Dynasore Suppresses mTORC1 Activity and Induces Autophagy to Regulate the Clearance of Protein Aggregates in Neurodegenerative Diseases
复制标题
Dynasore 抑制 mTORC1 活性并诱导自噬来调节神经退行性疾病中蛋白质聚集体的清除。
DOI：
10.1007/s12640-019-00027-9
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发表时间：
2019-07-01
影响因子：
3.7
通讯作者：
Wang, Hongfeng
中科院分区：
文献类型：
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作者：
Chen, Yang;Xu, Shiqiang;Wang, Hongfeng
自噬是一种重要的细胞蛋白质调控过程，在细胞内稳态的调节和包括神经退行性疾病在内的许多人类疾病的发病机制中起着关键作用。自噬活性降低和蛋白质聚集异常是神经退行性疾病的常见特征，包括阿尔茨海默病、帕金森病、肌萎缩侧索硬化和亨廷顿病。因此，整体自噬的药理学调控可能有助于有效治疗神经退行性疾病。在目前的研究中，我们发现Dynasore，一种有效的动力蛋白抑制剂，可以抑制mTOR的溶酶体定位和阻断mTORC 1的活性，这反过来又增强了自噬的主要调节因子包括TFE 3和TFEB的核转位。我们发现，自噬通量上调Dynasore处理的细胞。此外，Dynasore的处理显著促进了由含有扩展的多聚谷氨酰胺（polyQ）的突变亨廷顿蛋白形成的蛋白质聚集体的清除，但不促进受损的线粒体的清除。相比之下，Dynasore治疗对ATG 5缺失细胞中突变亨廷顿蛋白的polyQ聚集体的清除没有影响，其中自噬是缺陷的。总之，我们的研究结果表明，Dynasore通过调节mTORC 1-TFEB信号传导影响神经退行性疾病相关蛋白的自噬降解。
Autophagy is an important cellular protein control process, which plays a key role in the regulation of cell homeostasis and pathogenesis of many human diseases including neurodegenerative diseases. Reduced autophagic activity and abnormal protein aggregation are common features of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Therefore, pharmacological regulation of overall autophagy may be helpful for effective treatment of neurodegenerative diseases. In the present study, we find Dynasore, a potent inhibitor of dynamin, can repress the lysosomal localization of mTOR and block the activity of mTORC1, which in turn enhances the nuclear translocation of the master regulators of autophagy including TFE3 and TFEB. We find that autophagic flux is upregulated in Dynasore-treated cells. Moreover, treatment of Dynasore significantly promotes the clearance of protein aggregates formed by mutant huntingtin protein containing expanded polyglutamine (polyQ), but not damaged mitochondria. In contrast, treatment with Dynasore has no effect on the clearance of polyQ aggregates of mutant huntingtin in ATG5-depleted cells, in which autophagy is defective. Taken together, our results indicate that Dynasore affects autophagic degradation of neurodegenerative disease-associated proteins by regulating mTORC1-TFEB signaling.