JWA antagonizes paraquat-induced neurotoxicity via activation of Nrf2

X Zhao; R Wang; J Xiong; D Yan; A Li; S Wang; J Xu; J Zhou

doi:10.1016/j.toxlet.2017.04.011

JWA antagonizes paraquat-induced neurotoxicity via activation of Nrf2

Toxicol Lett. 2017 Aug 5:277:32-40. doi: 10.1016/j.toxlet.2017.04.011. Epub 2017 Apr 18.

Authors

X Zhao¹, R Wang¹, J Xiong¹, D Yan¹, A Li¹, S Wang¹, J Xu², J Zhou³

Affiliations

¹ Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of the Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, China.
² Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of the Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, China. Electronic address: [email protected].
³ Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of the Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, China. Electronic address: [email protected].

PMID: 28428137
DOI: 10.1016/j.toxlet.2017.04.011

Abstract

Paraquat (PQ), a widely used environmental toxin in agriculture, contributes to the onset and progression of Parkinson's disease (PD) by damaging neurons. The JWA gene, also known as ARL6IP5, exerts a protective effect on degenerating dopamine (DA) neurons. However, the roles of JWA in PQ-induced neuronal damage are still unknown. In our study, two neuronal cell lines (HT-22 and SH-SY5Y) and neuron-specific JWA knockout (JWA-nKO) and age-matched wild-type (JWA-nWT) mice were subjected to PQ treatment. The results indicate that PQ administration triggers the upregulation of JWA. Elevated expression of JWA rescues the accumulation of reactive oxygen species (ROS) while increasing glutathione (GSH) and glutathione peroxidase (GPx) levels under PQ exposure. Further investigations revealed that the protective effect of JWA mostly involves regulation of the MEK/PI3K-Nrf2 axis. Our results suggest that JWA may be a novel target for the prevention and treatment of PQ-induced PD.

Keywords: JWA; Neurotoxicity; Nrf2; Paraquat.

Publication types

Comparative Study

MeSH terms

Animals
Apoptosis / drug effects*
Behavior, Animal / drug effects
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Cell Line, Tumor
Dose-Response Relationship, Drug
Extracellular Signal-Regulated MAP Kinases / metabolism
Glutathione / metabolism
Glutathione Peroxidase / metabolism
HEK293 Cells
Heat-Shock Proteins / genetics
Heat-Shock Proteins / metabolism*
Herbicides / toxicity*
Humans
Inhibitory Concentration 50
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
MAP Kinase Kinase Kinases / metabolism
Membrane Transport Proteins
Mice, Knockout
Motor Activity / drug effects
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism*
Neurons / drug effects*
Neurons / metabolism
Neurons / pathology
Neurotoxicity Syndromes / etiology*
Neurotoxicity Syndromes / genetics
Neurotoxicity Syndromes / metabolism
Neurotoxicity Syndromes / physiopathology
Oxidative Stress / drug effects
Paraquat / toxicity*
Phosphatidylinositol 3-Kinase / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Reactive Oxygen Species / metabolism
Signal Transduction / drug effects
Transcription, Genetic
Transcriptional Activation
Transfection

Substances

ARL6IP5 protein, human
Arl6ip5 protein, mouse
Carrier Proteins
Heat-Shock Proteins
Herbicides
Intracellular Signaling Peptides and Proteins
Membrane Transport Proteins
NF-E2-Related Factor 2
NFE2L2 protein, human
Reactive Oxygen Species
Glutathione Peroxidase
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt
Extracellular Signal-Regulated MAP Kinases
MAP Kinase Kinase Kinases
Glutathione
Paraquat