Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons
Jie Sun, Xiaomin Lin, Dan-Hua Lu, Meng Wang, Kun Li, Shengrong Li, Zhengqiu Li, Chengjun Zhu, Zhimin Zhang, Chang‐Yu Yan, Ming‐Hai Pan, Haibiao Gong, Jing-Cheng Feng, Yun‐Feng Cao, Feng Huang, Wan‐Yang Sun, Hiroshi Kurihara, Yifang Li, Wen‐Jun Duan, Genlong Jiao, Li Zhang, Rong‐Rong He
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.