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Dynasore Suppresses mTORC1 Activity and Induces Autophagy to Regulate the Clearance of Protein Aggregates in Neurodegenerative Diseases

  • Yang Chen
  • Shiqiang Xu
  • Nana Wang
  • Qilian Ma
  • Panpan Peng
  • Yunhao Yu
  • Li Zhang
  • Zheng YingEmail author
  • Hongfeng WangEmail author
Original Article

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 TFEB Lysosome mTORC1 Neurodegenerative disease 

Notes

Funding Information

This work was supported by the National Key Plan for Scientific Research and Development of China (Nos. 2017YFC0909100), the National Natural Sciences Foundation of China (Nos. 31571053 and 31771117), a Project Funded by Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003), and a Project Funded by the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical SciencesSoochow UniversitySuzhouChina
  2. 2.School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of EducationYantai UniversityYantaiChina
  3. 3.Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College ofPharmaceutical SciencesSoochow UniversitySuzhouChina
  4. 4.Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear MedicineWuxiChina

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