摘要
铁在 Parkinson 的疾病(PD ) 起一个关键作用。substantia nigra (SN ) 的增加的铁内容在 PD 病人,和二价的金属 transporter 被发现了(DMT1 ) 1 被显示了在两个导致 MPTP 的 PD 模型和 PD 病人的 SN 起来调整。然而,位于 DMT1 起来规定下面的机制大部分是未知的。在现在的学习,我们观察到那在 6-hydroxydopamine ( 6-OHDA )的 SN 导致了 PD 老鼠,有铁的 DMT1 应答的元素(怒火, DMT1+IRE ),然而并非没有怒火( DMT1?IRE )的 DMT1 ,是起来调整的,建议那增加的 DMT1+IRE 表情可能在 PD 老鼠说明 nigral 铁累积。这可能性进一步被估计在一在里面 vitro 学习使用 6-OHDA-treated 和 DMT1+IRE-over-expressing MES23.5 房间。在 6-OHDA-treated MES23.5 房间,增加了铁规章的蛋白质(IRP ) 1 并且 IRP2 表示被观察,当 IRP 的 silencing 戏剧性地减少了时 6-OHDA-induced DMT1+IRE 起来规定。有 N-acetyl-L-cysteine 的预告的处理充分由 6-OHDA-induced 的抑制压制了 IRP 起来规定氧化应力。增加的 DMT1+IRE 表示由 MES23.5 房间导致了增加的铁流入。我们的数据提供 DMT1+IRE 起来规定能说明细胞内部的氧化应力和那增加了的 6-OHDA-induced 开始的 IRE/IRP-dependent 6-OHDA-induced 铁累积的直接证据细胞内部的铁的层次导致加重的氧化应力。这研究的结果提供在 PD 的处理支持抗氧化剂的使用的新奇证据,旨在禁止由 DMT1 表示的规定的铁累积。
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.
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).
关键词
转运蛋白
二价金属
爱尔兰
专家
中毒
divalent metal transporter 1, iron, iron regulatory protein, Parkinson's disease, oxidative stress, antioxidant