Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons
Jie Sun, … , Li Zhang, Rong-Rong He
Jie Sun, … , Li Zhang, Rong-Rong He
Published May 15, 2023
Citation Information: J Clin Invest. 2023;133(10):e165228. https://doi.org/10.1172/JCI165228.
View: Text | PDF
Research Article Cell biology Neuroscience

Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the gradual loss of midbrain dopaminergic neurons in association with aggregation of α-synuclein. Oxidative damage has been widely implicated in this disease, though the mechanisms involved remain elusive. Here, we demonstrated that preferential accumulation of peroxidized phospholipids and loss of the antioxidant enzyme glutathione peroxidase 4 (GPX4) were responsible for vulnerability of midbrain dopaminergic neurons and progressive motor dysfunctions in a mouse model of PD. We also established a mechanism wherein iron-induced dopamine oxidation modified GPX4, thereby rendering it amenable to degradation via the ubiquitin-proteasome pathway. In conclusion, this study unraveled what we believe to be a novel pathway for dopaminergic neuron degeneration during PD pathogenesis, driven by dopamine-induced loss of antioxidant GPX4 activity.

Authors

Jie Sun, Xiao-Min Lin, Dan-Hua Lu, Meng Wang, Kun Li, Sheng-Rong Li, Zheng-Qiu Li, Cheng-Jun Zhu, Zhi-Min Zhang, Chang-Yu Yan, Ming-Hai Pan, Hai-Biao Gong, Jing-Cheng Feng, Yun-Feng Cao, Feng Huang, Wan-Yang Sun, Hiroshi Kurihara, Yi-Fang Li, Wen-Jun Duan, Gen-Long Jiao, Li Zhang, Rong-Rong He

×

Figure 7

GPX4 attenuated α-synuclein-induced ferroptotic susceptibility.

Options: View larger image (or click on image) Download as PowerPoint
GPX4 attenuated α-synuclein-induced ferroptotic susceptibility. (A) Sche...
(A) Schematic diagram showing that 8-week-old WT mice were unilaterally injected with AAV-loaded human SNCA or GPX4 into the substantia nigra. Disordered motor coordination of SNCA mice was mitigated by GPX4, as displayed by behavioral tests (B) rotarod and (C) pole climbing. Statistics were determined by 2-way repeated measures ANOVA (n = 10 mice each group). (D and E) Catwalk gait analysis (n = 10 mice each group). (F) IHC of substantia nigra sections labeled with TH antibody and hematoxylin. Scale bar: 500 μm. (G) Western blotting (left) and quantitative analysis (right) of 4-HNE expression in midbrain (n = 6 mice each group). (H) MDA content was measured in midbrain (n = 6 mice each group). (I) Ferroptosis-related genes were detected by quantitative real-time PCR assay and the relative expressions were displayed as heatmap (n = 3 mice each group). (J) Western blotting (left) and quantitative analysis (right) of TH, TFRC and GPX4 expressions in midbrain (n = 6 mice each group). All data represent mean ± SEM. *P < 0.05, **P < 0.01 and ***P < 0.001, by 1-way ANOVA with Tukey’s HSD (for E and G) or Bonferroni’s posthoc (for H, and J) test.