Activation of p62-Keap1-Nrf2 Pathway Protects 6-Hydroxydopamine-Induced Ferroptosis in Dopaminergic Cells
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ORIGINAL ARTICLE
Activation of p62-Keap1-Nrf2 Pathway Protects 6-Hydroxydopamine-Induced Ferroptosis in Dopaminergic Cells Yiran Sun 1,2 & Libo He 1,2 & Taoyu Wang 1,2 & Wan Hua 1,2 & Huan Qin 1,2 & Jingjin Wang 1,2 & Li Wang 1,2 & Wanqin Gu 1,2 & Tingting Li 1,2 & Na Li 1,2 & Xinanbei Liu 1,2 & Fang Chen 1,2 & Lin Tang 1,2 Received: 8 May 2020 / Accepted: 28 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Parkinson’s disease (PD) is a common neurodegenerative disorder primarily caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). However, the manner of death of dopaminergic neurons remains indistinct. Ferroptosis is a form of cell death involving in the iron-dependent accumulation of glutathione depletion and lipid peroxide. Besides, previous studies indicated that ferroptosis might be involved in the death of dopaminergic neurons. In this study, we aim to explore the protective effect of the p62-Keap1-Nrf2 pathway against 6-hydroxydopamine (6-OHDA)-induced ferroptosis in dopaminergic cells. Firstly, our results demonstrated that 6-OHDA-induced ferroptosis could be observed in vivo zebrafish and in vitro human dopaminergic cell line (SH-SY5Y cells) model. Moreover, ferroptosis induced by 6-OHDA mitigates in SH-SY5Y cells upon ferrostatin-1 (Fer, an inhibitor of ferroptosis) treatment via upregulating the protein expression of glutathione peroxidase 4 (GPX4). Then, we found that high p62/SQSTM1 (p62) expression could protect SH-SY5Y cells against ferroptosis through promoting Nrf2 nuclear transfer and upregulating the expression of the antioxidant protein heme oxygenase-1 (HO-1). Ultimately, high p62 expression activates the Nrf2/HO-1 signaling pathway through binding to Kelch-like ECH-associated protein 1 (Keap1). Collectively, the activation of the p62-Keap1-Nrf2 pathway prevents 6-OHDA-induced ferroptosis in SHSY5Y cells, targeting this pathway in combination with a pharmacological inhibitor of ferroptosis can be a potential approach for PD therapy. Keywords Parkinson’s disease . 6-OHDA . Ferroptosis . p62-Keap1-Nrf2
Abbreviations PD Parkinson’s disease ROS Reactive oxygen species 6-OHDA 6-Hydroxydopamine Fer Ferrostatin-1 Yiran Sun, Libo He, Taoyu Wang and Wan Hua contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02049-3) contains supplementary material, which is available to authorized users.
HO-1 Nrf2 SNpc GPX4 ACSL4 α-syn Nec Keap1 ZnPP p62 BCA
Heme oxygenase-1 Nuclear factor erythroid 2-like 2 Substantia nigra pars compacta Glutathione peroxidase 4 Acyl-CoA synthetase-4 α-Synuclein Necrosulfonamide Kelch-like ECH-associated protein 1 Zn-protoporphyrin p62/SQSTM1 Bicinchoninic acid
* Lin Tang [email protected] 1
2
Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, China National and Local Joint Engineering Laboratory for Energy Plant Bio-Oi
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