Chronic carbon disulfide exposure induces parkinsonian pathology via α-synuclein aggregation and necrosome complex interaction
Zhidan Liu,
Kang Kang,
Shulin Shan,
Shuai Wang,
Xianjie Li,
Hui Yong,
Zhengcheng Huang,
Yiyu Yang,
Zhaoxiong Liu,
Yanan Sun,
Yao Bai,
Fuyong Song
Affiliations
Zhidan Liu
Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
Kang Kang
Qingdao Municipal Center for Disease Control & Prevention, Qingdao, Shandong 266033, China
Shulin Shan
Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
Shuai Wang
Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
Xianjie Li
Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou, Guangdong 510075, China
Hui Yong
Qingdao Municipal Center for Disease Control & Prevention, Qingdao, Shandong 266033, China
Zhengcheng Huang
Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
Yiyu Yang
Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
Zhaoxiong Liu
Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
Yanan Sun
Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing 100021, China
Yao Bai
NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing 100021, China; Corresponding author
Fuyong Song
Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Corresponding author
Summary: Exposure to carbon disulfide (CS2) has been associated with an increased incidence of parkinsonism in workers, but the mechanism underlying this association remains unclear. Using a rat model, we investigated the effects of chronic CS2 exposure on parkinsonian pathology. Our results showed that CS2 exposure leads to significant motor impairment and neuronal damage, including loss of dopaminergic neurons and degeneration of the substantia nigra pars compacta (SNpc). The immunoassays revealed that exposure to CS2 induces aggregation of α-synuclein and phosphorylated α-synuclein, as well as activation of necroptosis in the SNpc. Furthermore, in vitro and in vivo experiments demonstrated that the interaction between α-synuclein and the necrosome complex (RIP1, RIP3, and MLKL) is responsible for the loss of neuronal cells after CS2 exposure. Taken together, our results demonstrate that CS2-mediated α-synuclein aggregation can induce dopaminergic neuron damage and parkinsonian behavior through interaction with the necrosome complex.
