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DJ‐1 modulates the expression of Cu/Zn‐superoxide dismutase‐1 through the Erk1/2–Elk1 pathway in neuroprotection
Author(s) -
Wang Zhiquan,
Liu Jun,
Chen Siyan,
Wang Ying,
Cao Li,
Zhang Yu,
Kang Wenyan,
Li Hui,
Gui Yaxing,
Chen Shengdi,
Ding Jianqing
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22514
Subject(s) - gene knockdown , oxidative stress , sod1 , neuroprotection , superoxide dismutase , chemistry , reactive oxygen species , dopaminergic , microbiology and biotechnology , downregulation and upregulation , biology , biochemistry , endocrinology , pharmacology , dopamine , gene
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