Journal
CELL DEATH & DISEASE
Volume 11, Issue 2, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-020-2322-6
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Funding
- Macau Government [FDCT-092-2015-A3]
- University of Macau [MYRG2019-00129-ICMS, MYRG2017-00147-ICMS]
- Hong Kong Baptist University [EF001/ICMS-LJH/2015/HKBU]
- Hong Kong Government Research Grants [GRF/HKBU12100914, GRF/HKBU12101417]
- Hong Kong Baptist University Research Grants [F.R.G. I/15-16/042, FRG II/17-18/021]
- [NSFC-81773926]
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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.
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