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Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson’s disease models
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Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson’s disease models
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Journal Article
Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson’s disease models
2020
Overview
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.
Publisher
Nature Publishing Group UK,Springer Nature B.V
Subject
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/ 14/1
/ 14/19
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/ 14/63
/ 38
/ 38/77
/ 38/89
/ 42
/ Animals
/ Antiparkinson Agents - pharmacology
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
/ Behavior, Animal - drug effects
/ Biomedical and Life Sciences
/ Calcium
/ Curcumin
/ Curcumin - analogs & derivatives
/ Dopaminergic Neurons - drug effects
/ Dopaminergic Neurons - metabolism
/ Dopaminergic Neurons - pathology
/ Female
/ Humans
/ Naphthyridines - pharmacology
/ Neurons
/ Oxidative Stress - drug effects
/ Parkinsonian Disorders - chemically induced
/ Parkinsonian Disorders - drug therapy
/ Parkinsonian Disorders - metabolism
/ Parkinsonian Disorders - pathology
