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

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.