Cell stress induced by the parkinsonian mimetic, 6-hydroxydopamine, is concurrent with oxidation of the chaperone, ERp57, and aggresome formation
Cell stress induced by the parkinsonian mimetic, 6-hydroxydopamine, is concurrent with oxidation of the chaperone, ERp57, and aggresome formation
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DOI：
10.1089/ars.2007.1791
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发表时间：
2007-12-01
影响因子：
6.6
通讯作者：
O'Malley, Karen L.
中科院分区：
文献类型：
--
作者：
Kim-Han, Jeong Sook;O'Malley, Karen L.
帕金森病（PD）涉及黑质纹状体通路的不可逆变性。由于大多数PD病例是散发性的，环境风险因素可能是多巴胺能神经元神经变性的基础。其中一个因子是6-羟基多巴胺（6-OHDA），它被广泛用作帕金森病模拟物。研究表明，6-OHDA产生活性氧并诱导细胞应激、未折叠蛋白反应和凋亡。目前的研究结果表明，6-OHDA，而不是过氧化氢，MPP+，或鱼藤酮，导致快速形成高分子量的蛋白质二硫键异构酶相关蛋白3（ERp 57）的剂量和时间依赖性的方式。此外，ERp 57缀合物被N-乙酰半胱氨酸和谷胱甘肽阻断，表明它们代表蛋白质的氧化形式。令人惊讶的是，缀合物与DNA复合，因为用DNA酶处理减少了它们的外观。亚细胞分离表明，核和线粒体DNA与蛋白质。最后，毒素处理的ERp 57在多巴胺能细胞中迅速形成类攻击性小体结构，表明ERp 57在毒素介导的应激中起早期适应性反应。了解与帕金森病模拟物相关的信号传导机制，以及它们的时间诱导，可能有助于设计更好的PD模型干预措施。
Parkinson's disease (PD) involves an irreversible degeneration of the nigrostriatal pathway. As most cases of PD are sporadic, environmental risk factors may underlie neurodegeneration in dopaminergic neurons. One such factor is 6-hydroxydopamine (6-OHDA), which is widely used as a parkinsonian mimetic. Studies have shown that 6-OHDA generates reactive oxygen species and induces cell stress, the unfolded protein response, and apoptosis. Present findings show that 6-OHDA, but not hydrogen peroxide, MPP+, or rotenone, leads to the rapid formation of high-molecular-weight species of protein disulfide isomerase-associated protein 3 (ERp57) in a dose- and time-dependent fashion. Moreover, ERp57 conjugates are blocked by N-acetylcysteine and glutathione, suggesting that they represent oxidized forms of protein. Surprisingly, conjugates are complexed with DNA, because treatment with DNase reduces their appearance. Subcellular fractionation indicates that both nuclear and mitochondrial DNA are associated with the protein. Finally, toxin-treated ERp57 rapidly forms juxtanuclear aggresome-like structures in dopaminergic cells, suggesting that ERp57 plays an early adaptive response in toxin-mediated stress. Understanding the signaling mechanisms associated with parkinsonian mimetics, as well as their temporal induction, may aid in designing better interventions in models of PD.