From the Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan,; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Japan.
the Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan,; the Institute of Genome Research, Tokushima University, Tokushima 770-8503, Japan.
J Biol Chem. 2011 Mar 11;286(10):7947-7957. doi: 10.1074/jbc.M110.156430. Epub 2010 Dec 3.
Oxidative stress and endoplasmic reticulum (ER) stress are thought to contribute to the pathogenesis of various neurodegenerative diseases including Parkinson disease (PD), however, the relationship between these stresses remains unclear. ATF6α is an ER-membrane-bound transcription factor that is activated by protein misfolding in the ER and functions as a critical regulator of ER quality control proteins in mammalian cells. The goal of this study was to explore the cause-effect relationship between oxidative stress and ER stress in the pathogenesis of neurotoxin-induced model of PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a dopaminergic neurotoxin known to produce oxidative stress, activated ATF6α and increased ER chaperones and ER-associated degradation (ERAD) component in dopaminergic neurons. Importantly, MPTP induced formation of ubiquitin- immunopositive inclusions and loss of dopaminergic neurons more prominently in mice deficient in ATF6α than in wild-type mice. Cultured cell experiments revealed that 1-methyl-4-phenylpyridinium (MPP(+))-induced oxidative stress not only promoted phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) but also enhanced interaction between phosphorylated p38MAPK and ATF6α, leading to increment in transcriptional activator activity of ATF6α. Thus, our results revealed a link between oxidative stress and ER stress by showing the importance of ATF6α in the protection of the dopaminergic neurons from MPTP that occurs through oxidative stress-induced activation of ATF6α and p38MAPK-mediated enhancement of ATF6α transcriptional activity.
氧化应激和内质网（ER）应激被认为有助于包括帕金森病（PD）在内的各种神经退行性疾病的发病机制，但这两种应激之间的关系尚不清楚。ATF6α 是一种 ER 膜结合转录因子，当 ER 中的蛋白质错误折叠时被激活，并在哺乳动物细胞中作为 ER 质量控制蛋白的关键调节剂发挥作用。本研究的目的是探讨神经毒素诱导的 PD 模型发病机制中氧化应激和 ER 应激之间的因果关系。1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）是一种已知会产生氧化应激的多巴胺能神经毒素，它激活了 ATF6α，并增加了多巴胺能神经元中的 ER 伴侣和 ER 相关降解（ERAD）成分。重要的是，与野生型小鼠相比，ATF6α 缺失的小鼠中，MPTP 诱导的泛素免疫阳性包涵体形成和多巴胺能神经元丢失更为明显。培养细胞实验表明，1-甲基-4-苯基吡啶鎓（MPP(+)）诱导的氧化应激不仅促进了 p38 丝裂原激活蛋白激酶（p38MAPK）的磷酸化，还增强了磷酸化的 p38MAPK 与 ATF6α 之间的相互作用，导致 ATF6α 的转录激活剂活性增加。因此，我们的研究结果通过显示 ATF6α 在保护多巴胺能神经元免受 MPTP 损伤中的重要性，揭示了氧化应激和 ER 应激之间的联系，这种保护作用是通过氧化应激诱导的 ATF6α 激活和 p38MAPK 介导的 ATF6α 转录活性增强来实现的。
