PUBLICATION
Activation of p62-Keap1-Nrf2 Pathway Protects 6-Hydroxydopamine-Induced Ferroptosis in Dopaminergic Cells
- Authors
- Sun, Y., He, L., Wang, T., Hua, W., Qin, H., Wang, J., Wang, L., Gu, W., Li, T., Li, N., Liu, X., Chen, F., Tang, L.
- ID
- ZDB-PUB-200810-39
- Date
- 2020
- Source
- Molecular neurobiology 57(11): 4628-4641 (Journal)
- Registered Authors
- Keywords
- 6-OHDA, Ferroptosis, Parkinson’s disease, p62-Keap1-Nrf2
- MeSH Terms
-
- Animals
- Cell Line
- Cyclohexylamines/pharmacology
- Dopaminergic Neurons/drug effects
- Dopaminergic Neurons/metabolism*
- Dopaminergic Neurons/pathology*
- Ferroptosis*
- Heme Oxygenase-1/metabolism
- Kelch-Like ECH-Associated Protein 1/metabolism*
- Models, Biological
- NF-E2-Related Factor 2/metabolism*
- Neuroprotection*/drug effects
- Oxidopamine
- Phenylenediamines/pharmacology
- Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
- Protein Binding/drug effects
- Sequestosome-1 Protein/metabolism*
- Signal Transduction*/drug effects
- Zebrafish
- PubMed
- 32770451 Full text @ Mol. Neurobiol.
Citation
Sun, Y., He, L., Wang, T., Hua, W., Qin, H., Wang, J., Wang, L., Gu, W., Li, T., Li, N., Liu, X., Chen, F., Tang, L. (2020) Activation of p62-Keap1-Nrf2 Pathway Protects 6-Hydroxydopamine-Induced Ferroptosis in Dopaminergic Cells. Molecular neurobiology. 57(11):4628-4641.
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 SH-SY5Y cells, targeting this pathway in combination with a pharmacological inhibitor of ferroptosis can be a potential approach for PD therapy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping