Tristetraprolin destabilizes NOX2 mRNA and protects dopaminergic neurons from oxidative damage in Parkinson's disease.

Xiang Sun, Hongbo Zhang, Linghai Xie, Chen Qian, Yongyi Ye, Hengxu Mao, Baoyan Wang, Huan Zhang, Yizhou Zhang, Xiaozheng He, Shizhong Zhang

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2020 Nov

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Tristetraprolin (TTP), an RNA-binding protein encoded by the ZFP36 gene, is vital for neural differentiation; however, its involvement in neurodegenerative diseases such as Parkinson's disease (PD) remains unclear. To explore the role of TTP in PD, an in vitro 1-methyl-4-phenylpyridinium (MPP+ ) cell model and an in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of PD were used. Transfection of small interfering (si)-TTP RNA upregulated pro-oxidative NOX2 expression and ROS formation, downregulated anti-oxidative GSH and SOD activity；si-TTP upregulated pro-apoptotic cleaved-caspase-3 expression, and downregulated antiapoptotic Bcl-2 expression; while overexpression (OE)-TTP lentivirus caused opposite effects. Through database prediction, luciferase experiment, RNA immunoprecipitation (RIP), and mRNA stability analysis, we evaluated the potential binding sites of TTP to 3'-untranslated regions (3'-UTR) of NOX2 mRNA. TTP affected the NOX2 luciferase activity by binding to two sites in the NOX2 3'-UTR. RIP-qPCR confirmed TTP binding to both sites, with a higher affinity for site-2. In addition, TTP reduced the NOX2 mRNA stability. si-NOX2 and antioxidant N-acetyl cysteine (NAC) reversed si-TTP-induced cell apoptosis. In MPTP-treated mice, TTP expression increased and was co-located with dopaminergic neurons. TTP also inhibited NOX2 and decreased the oxidative stress in vivo. In conclusion, TTP protects against dopaminergic oxidative injury by promoting NOX2 mRNA degradation in the MPP+ /MPTP model of PD, suggesting that TTP could be a potential therapeutic target for regulating the oxidative stress in PD. © 2020 Federation of American Societies for Experimental Biology.

Citation

Xiang Sun, Hongbo Zhang, Linghai Xie, Chen Qian, Yongyi Ye, Hengxu Mao, Baoyan Wang, Huan Zhang, Yizhou Zhang, Xiaozheng He, Shizhong Zhang. Tristetraprolin destabilizes NOX2 mRNA and protects dopaminergic neurons from oxidative damage in Parkinson's disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020 Nov;34(11):15047-15061