Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent
Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent
复制标题
6-羟基多巴胺中毒时二价金属转运蛋白 1 的上调依赖于 IRE/IRP。
DOI：
10.1038/cr.2010.20
复制
发表时间：
2010-03-01
期刊：
影响因子：
44.1
通讯作者：
Xie, Junxia
中科院分区：
文献类型：
--
作者：
Jiang, Hong;Song, Ning;Xie, Junxia
铁在帕金森病（PD）中起着关键作用。在PD患者中发现黑质（SN）铁含量增加，并且已显示二价金属转运蛋白1（DMT 1）在MPTP诱导的PD模型和PD患者的SN中上调。然而，DMT 1上调的潜在机制在很大程度上是未知的。在本研究中，我们观察到，在6-羟基多巴胺（6-OHDA）诱导的PD大鼠的黑质中，具有铁反应元件（IRE，DMT 1 +IRE）的DMT 1，而不是没有IRE的DMT 1（DMT 1-IRE），被上调，这表明DMT 1 +IRE表达增加可能是PD大鼠黑质铁积累的原因。在使用6-OHDA处理的和DMT 1 + IRE过表达的MES 23.5细胞的体外研究中进一步评估了这种可能性。在6-OHDA处理的MES23.5细胞中，观察到铁调节蛋白（IRP）1和IRP 2表达增加，而IRP的沉默显著降低了6-OHDA诱导的DMT 1 +IRE上调。用N-乙酰-L-半胱氨酸预处理通过抑制6-OHDA诱导的氧化应激完全抑制IRP的上调。DMT 1 +IRE表达增加导致MES 23.5细胞铁内流增加。我们的数据提供了直接的证据，DMT 1 +IRE上调可以解释IRE/IRP依赖性6-OHDA诱导的铁积累开始由6-OHDA诱导的细胞内氧化应激和细胞内铁水平的增加导致加重氧化应激。这项研究的结果提供了新的证据，支持在PD治疗中使用抗氧化剂，其目的是通过调节DMT 1表达来抑制铁积累。
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, DMT1+IRE), but not DMT1 without IRE (DMT1-IRE), was upregulated, suggesting that increased DMT1+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 DMT1+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-induced DMT1+IRE up-regulation. Pretreatment with N-acetyl-l-cysteine fully suppressed IRPs up-regulation by inhibition of 6-OHDA-induced oxidative stress. Increased DMT1+IRE expression resulted in increased iron influx by MES23.5 cells. Our data provide direct evidence that DMT1+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 aggravated 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.