2. Academic Validation
  3. 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

  • Neurotox Res. 2019 Jul;36(1):108-116. doi: 10.1007/s12640-019-00027-9.
Yang Chen 1,  Shiqiang Xu 1,  Nana Wang 1,  Qilian Ma 1,  Panpan Peng 1,  Yunhao Yu 1,  Li Zhang 2,  Zheng Ying 3 4 5,  Hongfeng Wang 6
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China.
  • 2 Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, 214063, China.
  • 3 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China. zheng.ying@suda.edu.cn.
  • 4 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China. zheng.ying@suda.edu.cn.
  • 5 Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College ofPharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215021, China. zheng.ying@suda.edu.cn.
  • 6 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, China. wanghongfeng@suda.edu.cn.
PMID: 30924108 DOI: 10.1007/s12640-019-00027-9
Abstract

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.

Keywords

Autophagy; Lysosome; Neurodegenerative disease; TFEB; mTORC1.

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