Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent  

作　　者：Hong Jiang Ning Song Huamin Xu Shuzhen Zhang Jun Wang Junxia Xie 

机构地区：[1]Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders andState Key Disciplines.' Physiology, Medical College of Qingdao University, Qingdao 266071, China

出　　处：《Cell Research》2010年第3期345-356,共12页细胞研究（英文版）

基　　金：We thank Dr Wei-dong Le for providing the MES23.5 cell line. This work was supported by grants from the National Program of Basic Research sponsored by the Ministry of Science and Tech- nology of China （2006CB500704）, the National Natural Science Foundation of China （30930036, 30770757, 30870858） and the Natural Science Fund of Shandong Province for Distinguished Young Scholars （JQ200807）.

摘　　要：Iron plays a key role in Parkinson＇s disease （PD）. Increased iron content of the substantia nigra （SN） has been found in PD patients, and divalent metal transporter 1 （DMT1） has been shown to be up-regulated in the SN of both MPTP-induced PD models and PD patients. However, the mechanisms underlying DMT1 up-regulation are largely unknown. In the present study, we observed that in the SN of 6-hydroxydopamine （6-OHDA）-induced PD rats, DMT1 with the iron responsive element （IRE, DMTI＋IRE）, but not DMT1 without IRE （DMTI-IRE）, was up- regulated, suggesting that increased DMTI＋IRE expression might account for nigral iron accumulation in PD rats. This possibility was further assessed in an in vitro study using 6-OHDA-treated and DMTl＋IRE-over-expressing MES23.5 cells. In 6-OHDA-treated MES23.5 cells, increased iron regulatory protein （IRP） 1 and IRP2 expression was observed, while silencing of IRPs dramatically diminished 6-OHDA-indueed DMTI＋IRE up-regulation. Pre- treatment with N-acetyl-L-cysteine fully suppressed IRPs up-regulation by inhibition of 6-OHDA-indueed oxidative stress. Increased DMTI＋IRE expression resulted in increased iron influx by MES23.5 cells. Our data provide direct evidence that DMTI＋IRE up-regulation can account for IRE/IRP-dependent 6-OHDA-induced iron accumulation initiated by 6-OHDA-induced intracellular oxidative stress and that increased levels of intracellular iron result in ag- gravated oxidative stress. The results of this study provide novel evidence supporting the use of anti-oxidants in the treatment of PD, with the goal of inhibiting iron accumulation by regulation of DMT1 expression.

关 键 词：divalent metal transporter 1 iron iron regulatory protein Parkinson＇s disease oxidative stress ANTIOXIDANT 

分 类 号：Q513[生物学—生物化学] TQ323.7[化学工程—合成树脂塑料工业]