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Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson’s disease models
Zhuang,Xu Xu1; Wang,Sheng Fang1; Tan,Yuan1; Song,Ju Xian2,3; Zhu,Zhou2; Wang,Zi Ying2; Wu,Ming Yue1; Cai,Cui Zan1; Huang,Zhi Jian1; Tan,Jie Qiong4; Su,Huan Xing1; Li,Min2; Lu,Jia Hong1
2020-02-01
Source PublicationCell Death and Disease
Volume11Issue:2
AbstractAutophagy, 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.
DOI10.1038/s41419-020-2322-6
URLView the original
Language英语
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Cited Times [WOS]:10   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macau,Macao
2.Mr. and Mrs. Ko Chi Ming Centre for Parkinson’s Disease Research,School of Chinese Medicine,Hong Kong Baptist University,Hong Kong
3.Medical College of Acupuncture-Moxibustion and Rehabilitation,Guangzhou University of Chinese Medicine,Guangzhou,China
4.Center for Medical Genetics,School of Life Sciences,Central South University,Changsha,China
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Zhuang,Xu Xu,Wang,Sheng Fang,Tan,Yuan,et al. Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson’s disease models[J]. Cell Death and Disease,2020,11(2).
APA Zhuang,Xu Xu.,Wang,Sheng Fang.,Tan,Yuan.,Song,Ju Xian.,Zhu,Zhou.,...&Lu,Jia Hong.(2020).Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson’s disease models.Cell Death and Disease,11(2).
MLA Zhuang,Xu Xu,et al."Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson’s disease models".Cell Death and Disease 11.2(2020).
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