6PPD-quinone exposure induces neuronal mitochondrial dysfunction to exacerbate Lewy neurites formation induced by α-synuclein preformed fibrils seeding

• Published in: Journal of hazardous materials Vol. 465; p. 133312
• Main Authors: Fang, Jiacheng, Wang, Xiaoxiao, Cao, Guodong, Wang, Fuyue, Ru, Yi, Wang, Bolun, Zhang, Yanhao, Zhang, Doudou, Yan, Jie, Xu, Ji, Ji, Jing, Ji, Fenfen, Zhou, Yingyan, Guo, Lei, Li, Min, Liu, Wenlan, Cai, Xiaodong, Cai, Zongwei
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.03.2024
• Subjects: Cerebrospinal fluid; Metabolomics; Mitochondrial respiration; N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone; α-synuclein preformed fibrils; Mitochondrial respiration; Metabolomics; N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone; Cerebrospinal fluid; α-synuclein preformed fibrils
• ISSN: 0304-3894; 1873-3336; 1873-3336
• DOI: 10.1016/j.jhazmat.2023.133312

The emerging toxicant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPD-Q) is of wide concern due to its ubiquitous occurrence and high toxicity. Despite regular human exposure, limited evidence exists about its presence in the body and potential health risks. Herein, we analyzed cerebrospinal fluid (CSF) samples from Parkinson's disease (PD) patients and controls. The CSF levels of 6PPD-Q were twice as high in PD patients compared to controls. Immunostaining assays performed with primary dopaminergic neurons confirm that 6PPD-Q at environmentally relevant concentrations can exacerbate the formation of Lewy neurites induced by α-synuclein preformed fibrils (α-syn PFF). Assessment of cellular respiration reveals a considerable decrease in neuronal spare respiratory and ATP-linked respiration, potentially due to changes in mitochondrial membrane potential. Moreover, 6PPD-Q-induced mitochondrial impairment correlates with an upsurge in mitochondrial reactive oxygen species (mROS), and Mito-TEMPO-driven scavenging of mROS can lessen the amount of pathologic phospho-serine 129 α-synuclein. Untargeted metabolomics provides supporting evidence for the connection between 6PPD-Q exposure and changes in neuronal metabolite profiles. In-depth targeted metabolomics further unveils an overall reduction in glycolysis metabolite pool and fluctuations in the quantity of TCA cycle intermediates. Given its potentially harmful attributes, the presence of 6PPD-Q in human brain could potentially be a risk factor for PD. [Display omitted] •The concentration of 6PPD-Q in the CSF of PD patients is twice as high as that in the control group•6PPD-Q exposure to neurons can exacerbate the formation of Lewy neurites induced by α-syn PFF•6PPD-Q and α-Syn PFF act synergistically to induce mitochondrial dysfunction•Exposing neurons to 6PPD-Q lowers the glycolysis metabolite pool and leads to changes in TCA cycle intermediates