DJ-1 modulates the expression of Cu/Zn-superoxide dismutase-1 through the Erk1/2-Elk1 pathway in neuroprotection

• Published in: Annals of neurology Vol. 70; no. 4; pp. 591 - 599
• Main Authors: Wang, Zhiquan, Liu, Jun, Chen, Siyan, Wang, Ying, Cao, Li, Zhang, Yu, Kang, Wenyan, Li, Hui, Gui, Yaxing, Chen, Shengdi, Ding, Jianqing
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2011; Wiley-Liss; Wiley Subscription Services, Inc
• Subjects: Animals; Biological and medical sciences; Cell Line, Transformed; ets-Domain Protein Elk-1 - genetics; ets-Domain Protein Elk-1 - metabolism; Female; HEK293 Cells; Humans; Injuries of the nervous system and the skull. Diseases due to physical agents; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; MAP Kinase Signaling System - genetics; Medical research; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Mutation; Neurology; Neurons - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oxidative Stress - genetics; Parkinson Disease - metabolism; Protein Deglycase DJ-1; Rodents; Saliva - metabolism; Superoxide Dismutase - metabolism; Transfection; Translocation, Genetic; Traumas. Diseases due to physical agents; Superoxide dismutase; Nervous system diseases; Oxidoreductases; Enzyme
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.22514

Objective: Loss of function mutations of Park7/DJ‐1 gene increase the susceptibility of dopaminergic cells to reactive oxygen species and cause early onset familial Parkinson disease (PD). However, the mechanisms underlying dopaminergic neuron loss related to DJ‐1 mutation remain undefined. Therefore, it is important to find the new mechanisms underlying the antioxidative functions of DJ‐1. Methods: DJ‐1 knockdown cells and DJ‐1 knockout mice were used to elucidate the mechanisms underlying the antioxidative stress of DJ‐1. Preliminary study of the saliva from PD patients and controls was used to confirm our findings obtained from the above studies. Results: Our experiments showed that DJ‐1 interacted with Erk1/2 and was required for the nuclear translocation of Erk1/2 upon oxidative stimulation. The translocation of Erk1/2 activated Elk1 and sequentially promoted superoxide dismutase1 (SOD1) expression. The nuclear translocation of Erk1/2, the activation of Elk1, and the ensuing upregulation of SOD1 were all suppressed in DJ‐1 knockdown cells and DJ‐1 null mice treated with oxidative insult. Furthermore, reintroduction of SOD1 into DJ‐1 knockdown cells protected them against oxidative stress. Finally, in the preliminary study, we found close correlation between the protein levels of DJ‐1 and SOD1 in the saliva samples from different stages of PD patients. Interpretation: Our studies suggest that DJ‐1 regulates SOD1 expression through Erk1/2–Elk1 pathway in its protective response to oxidative insult. ANN NEUROL 2011