Cell death caused by the synergistic effects of zinc and dopamine is mediated by a stress sensor gene Gadd45b - implication in the pathogenesis of Parkinson's disease

详细信息    查看全文

• 作者：Tien-Chun Yang ; Pei-Chun Wu ; I-Fang Chung ; Jhih-Hang Jiang ; Ming-Ji Fann and Lung-Sen Kao
• 刊名：Journal of Neurochemistry
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：139
• 期：1
• 页码：120-133
• 全文大小：1390K
• ISSN：1471-4159

文摘

The pathogenesis of Parkinson's disease (PD) is not completely understood, Zinc (Zn²⁺) and dopamine (DA) have been shown to involve in the degeneration of dopaminergic cells. By microarray analysis, we identified Gadd45b as a candidate molecule that mediates Zn²⁺ and DA-induced cell death; the mRNA and protein levels of Gadd45b are increased by Zn²⁺ treatment and raised to an even higher level by Zn²⁺ plus DA treatment. Zn²⁺ plus DA treatment-induced PC12 cell death was enhanced when there was over-expression of Gadd45b and was decreased by knock down of Gadd45b. MAPK p38 and JNK signaling was able to cross-talk with Gadd45b during Zn²⁺ and DA treatment. The synergistic effects of Zn²⁺ and DA on PC12 cell death can be accounted for by an activation of the Gadd45b-induced cell death pathway and an inhibition of p38/JNK survival pathway. Furthermore, the in vivo results show that the levels of Gadd45b protein expression and phosphorylation of p38 were increased in the substantia nigra by the infusion of Zn²⁺/DA in the mouse brain and the level of Gadd45b mRNA is significantly higher in the substantia nigra of male PD patients than normal controls. The novel role of Gadd45b and its interactions with JNK and p38 will help our understanding of the pathogenesis of PD and help the development of future treatments for PD.