JWA antagonizes paraquat-induced neurotoxicity via activation of Nrf2.

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.

• Authors: X Zhao, R Wang, J Xiong, D Yan, A Li, S Wang, J Xu, J Zhou
• Journal: Toxicology letters (Toxicol Lett) Vol. 277 Pg. 32-40 (Aug 05 2017) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 28428137 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2017. Published by Elsevier B.V.

Chemical References

• 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

Topics

• Animals
• Apoptosis (drug effects)
• Behavior, Animal (drug effects)
• Carrier Proteins (genetics, 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, metabolism)
• Herbicides (toxicity)
• Humans
• Inhibitory Concentration 50
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• MAP Kinase Kinase Kinases (metabolism)
• Membrane Transport Proteins
• Mice, Knockout
• Motor Activity (drug effects)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Neurons (drug effects, metabolism, pathology)
• Neurotoxicity Syndromes (etiology, genetics, metabolism, 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