Changes in iron-regulatory gene expression occur in human cell culture models of Parkinson's disease
Changes in iron-regulatory gene expression occur in human cell culture models of Parkinson's disease
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DOI：
10.1016/j.neuint.2011.05.006
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发表时间：
2011-08-01
影响因子：
4.2
通讯作者：
Hanemann, C. O.
中科院分区：
文献类型：
--
作者：
Carroll, C. B.;Zeissler, M. -L.;Hanemann, C. O.
背景资料：神经元铁积累被认为与帕金森病（PD）的发病机制有关，但其机制仍不清楚。我们推测功能性线粒体铁缺乏可能会刺激神经元铁摄取。毒素1-甲基-4-苯基碘化吡啶（MPP+）导致铁输入蛋白和铁转运蛋白进入线粒体的上调，其次是具有不同作用机制的毒素是否诱导表达的类似变化。我们采用定量PCR和Western印迹法研究了铁转运蛋白、二价金属转运蛋白、转铁蛋白受体1和2在分化的SH-SY 5 Y细胞中暴露于与PD、MPP+、百草枯相关的三种不同毒素（TfR 1和TfR 2）和线粒体铁蛋白-2和铁转运蛋白（ferroportin）（一种自由基发生剂）和lactacystin结果：MPP+可使参与细胞铁输入和转运到线粒体的基因的mRNA和蛋白水平增加。在接触另一种氧化应激诱导剂百草枯后也发生了类似的变化。Lactacystin也导致TfR 1 mRNA水平的增加，虽然其他的变化没有发现。结论：我们的研究结果支持一个功能线粒体铁赤字驱动神经元铁摄取的假设，但也表明，不同毒素诱导的神经元铁处理存在差异。(C)2011 Elsevier B. V.保留所有权利。
Background: Neuronal iron accumulation is thought to be relevant to the pathogenesis of Parkinson's disease (PD), although the mechanism remains elusive. We hypothesized that neuronal iron uptake may be stimulated by functional mitochondrial iron deficiency.Objective: To determine firstly whether the mitochondria! toxin, 1-methyl-4-phenylpyridinium iodide (MPP+), results in upregulation of iron-import proteins and transporters of iron into the mitochondria, and secondly whether similar changes in expression are induced by toxins with different mechanisms of action.Methods: We used quantitative PCR and Western blotting to investigate expression of the iron importers, divalent metal transporter, transferrin receptor 1 and 2 (TfR1 and TfR2) and mitoferrin-2 and the iron exporter ferroportin in differentiated SH-SY5Y cells exposed to three different toxins relevant to PD, MPP+, paraquat (a free radical generator) and lactacystin (an inhibitor of the ubiquitin-proteasome system (UPS)).Results: MPP+ resulted in increased mRNA and protein levels of genes involved in cellular iron import and transport into the mitochondria. Similar changes occurred following exposure to paraquat, another inducer of oxidative stress. Lactacystin also resulted in increased TfR1 mRNA levels, although the other changes were not found.Conclusion: Our results support the hypothesis of a functional mitochondrial iron deficit driving neuronal iron uptake but also suggest that differences exist in neuronal iron handling induced by different toxins. (C) 2011 Elsevier B.V. All rights reserved.