TY - JOUR
T1 - 6PPD-quinone exposure induces neuronal mitochondrial dysfunction to exacerbate Lewy neurites formation induced by α-synuclein preformed fibrils seeding
AU - Fang, Jiacheng
AU - Wang, Xiaoxiao
AU - Cao, Guodong
AU - Wang, Fuyue
AU - Ru, Yi
AU - Wang, Bolun
AU - Zhang, Yanhao
AU - Zhang, Doudou
AU - Yan, Jie
AU - Xu, Ji
AU - Ji, Jing
AU - Ji, Fenfen
AU - Zhou, Yingyan
AU - Guo, Lei
AU - Li, Min
AU - Liu, Wenlan
AU - Cai, Xiaodong
AU - Cai, Zongwei
N1 - The authors would like to acknowledge the financial support from the Collaborative Research Fund (No. C2011–21GF), Guangdong Province Basic and Applied Basic Research Foundation (No. 2021B1515120051), Hong Kong General Research Fund (No. 12302722) and from National Natural Science Foundation of China (No. 22306150).
Publisher Copyright:
© 2023
PY - 2024/3/5
Y1 - 2024/3/5
N2 - 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.
AB - 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.
KW - Cerebrospinal fluid
KW - Metabolomics
KW - Mitochondrial respiration
KW - N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone
KW - α-synuclein preformed fibrils
UR - http://www.scopus.com/inward/record.url?scp=85180545741&partnerID=8YFLogxK
U2 - 10.1016/j.jhazmat.2023.133312
DO - 10.1016/j.jhazmat.2023.133312
M3 - Journal article
AN - SCOPUS:85180545741
SN - 0304-3894
VL - 465
JO - Journal of Hazardous Materials
JF - Journal of Hazardous Materials
M1 - 133312
ER -