The Endoplasmic Reticulum Stress Sensor, ATF6α, Protects against Neurotoxin-induced Dopaminergic Neuronal Death
The Endoplasmic Reticulum Stress Sensor, ATF6α, Protects against Neurotoxin-induced Dopaminergic Neuronal Death
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DOI：
10.1074/jbc.m110.156430
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发表时间：
2011-03-11
影响因子：
4.8
通讯作者：
Takahashi, Ryosuke
中科院分区：
文献类型：
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作者：
Egawa, Naohiro;Yamamoto, Keisuke;Takahashi, Ryosuke
氧化应激和内质网应激被认为与包括帕金森病(PD)在内的多种神经退行性疾病的发病有关，然而，这些应激之间的关系尚不清楚。ATF6α是一种内质网膜结合的转录因子，由内质网中的蛋白质错误折叠激活，是哺乳动物细胞中内质网质量控制蛋白的关键调节因子。本研究旨在探讨氧化应激与内质网应激在神经毒素诱导的帕金森病发病机制中的因果关系。1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)是一种已知可产生氧化应激的多巴胺能神经毒素，它能激活ATF6α，增加多巴胺能神经元中ER伴侣和ER相关降解(ERAD)成分。重要的是，MPTP在ATF6α缺陷小鼠中比野生型小鼠更显著地诱导泛素免疫阳性包涵体的形成和多巴胺能神经元的丢失。培养细胞实验表明，1-甲基-4-苯基吡啶(MPP+)诱导的氧化应激不仅促进了p38丝裂原活化蛋白激酶(P38MAPK)的磷酸化，而且增强了磷酸化的p38MAPK与ATF6α之间的相互作用，导致ATF6α转录激活活性增加。因此，我们的结果揭示了氧化应激和内质网应激之间的联系，表明ATF6α在保护多巴胺能神经元免受MPTP的影响中的重要性，MPTP是通过氧化应激诱导ATF6α的激活和p38MAPK介导的ATF6α转录活性的增强而发生的。
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. ATF6 alpha 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 ATF6 alpha 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 ATF6 alpha 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 ATF6 alpha, leading to increment in transcriptional activator activity of ATF6 alpha. Thus, our results revealed a link between oxidative stress and ER stress by showing the importance of ATF6 alpha in the protection of the dopaminergic neurons from MPTP that occurs through oxidative stress-induced activation of ATF6 alpha and p38MAPK-mediated enhancement of ATF6 alpha transcriptional activity.