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

doi:10.1016/j.isci.2023.107787

Chronic carbon disulfide exposure induces parkinsonian pathology via α-synuclein aggregation and necrosome complex interaction

iScience. 2023 Aug 30;26(10):107787. doi: 10.1016/j.isci.2023.107787. eCollection 2023 Oct 20.

Authors

Zhidan Liu¹, Kang Kang², Shulin Shan¹, Shuai Wang¹, Xianjie Li³, Hui Yong², Zhengcheng Huang¹, Yiyu Yang¹, Zhaoxiong Liu¹, Yanan Sun^{1

4}, Yao Bai⁴, Fuyong Song¹

Affiliations

¹ Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
² Qingdao Municipal Center for Disease Control & Prevention, Qingdao, Shandong 266033, China.
³ Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou, Guangdong 510075, China.
⁴ NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing 100021, China.

Abstract

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.

Keywords: Biochemistry; Biological sciences; Cell biology; Neuroscience.