Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson’s disease models
Autor: | Min Li, Xu-Xu Zhuang, Ju-Xian Song, Zhou Zhu, Yuan Tan, Zhijian Huang, Jieqiong Tan, Jia-Hong Lu, Cui-Zan Cai, Huanxing Su, Zi-Ying Wang, Sheng-Fang Wang, Ming-Yue Wu |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Cell death
Cancer Research Programmed cell death Curcumin Parkinson's disease Immunology ATG5 Oxidative phosphorylation Ascorbic Acid medicine.disease_cause Neuroprotection Article Antiparkinson Agents Cellular and Molecular Neuroscience Parkinsonian Disorders Cell Line Tumor Macroautophagy medicine Autophagy Animals Humans Naphthyridines lcsh:QH573-671 Oxidopamine Behavior Animal Chemistry Basic Helix-Loop-Helix Leucine Zipper Transcription Factors lcsh:Cytology Dopaminergic Neurons TOR Serine-Threonine Kinases Mitophagy Brain Cell Biology Ascorbic acid Cell biology Mice Inbred C57BL Disease Models Animal Oxidative Stress nervous system TFEB Female Oxidative stress Signal Transduction |
Zdroj: | Cell Death and Disease, Vol 11, Iss 2, Pp 1-18 (2020) Cell Death & Disease |
ISSN: | 2041-4889 |
Popis: | Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson’s disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions. |
Databáze: | OpenAIRE |
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