Deletion of Atf6α enhances kainate-induced neuronal death in mice
Deletion of Atf6α enhances kainate-induced neuronal death in mice
复制标题
DOI：
10.1016/j.neuint.2015.12.009
复制
发表时间：
2016-01-01
影响因子：
4.2
通讯作者：
Hori, Osamu
中科院分区：
文献类型：
--
作者：
Kezuka, Dai;Tkarada-Iemata, Mika;Hori, Osamu
大脑中过量的L-谷氨酸会导致各种病理状态下的神经元损伤，包括癫痫和中风。我们以前报道过，150 kDa的氧调节蛋白（ORP 150），内质网（ER）的分子伴侣，抑制L-谷氨酸诱导的神经元死亡，至少部分，通过改善钙稳态的ER。在本研究中，我们分析了激活转录因子6 α的作用。(ATF6α），一种对ER的操作至关重要的上游转录因子。在野生型（WT）小鼠中注射KA后，编码分子伴侣78 kDa葡萄糖调节蛋白（GRP 78）的Hspa 5的表达增加。使用WT和Atf 6 alpha（-/-）小鼠的比较分析显示，MA在Atf 6 alpha（-/-）小鼠的CA 3区诱导明显的神经元死亡。Atf 6 alpha（-/-）小鼠中神经元死亡的增加与ER中分子伴侣的表达减少和海马神经元中c-fos的显著诱导相关。此外，在KA注射后，注射兰尼碱受体抑制剂丹曲林部分挽救了Atf 6 α（-/-）小鼠的这些效应。我们的研究结果表明，ATF 6 α在KA诱导的兴奋性毒性后神经元的存活中起着重要作用，通过调节Ca 2+反应和神经元活性。(C)2015爱思唯尔有限公司版权所有。
Excessive amount of L-glutamate in the brain causes neuronal damage in various pathological conditions including epilepsy and stroke. We previously reported that the 150-kDa oxygen-regulated protein (ORP150), a molecular chaperone in the endoplasmic reticulum (ER), inhibited the L-glutamate-induced neuronal death, at least partly, by improving Ca2+ homeostasis in the ER. In the present study, we analyzed the role of activating transcription factor 6 alpha. (ATF6 alpha), an upstream transcriptional factor critical for the operation of the ER, using mouse intrahippocampal kainate (KA) injection model. Expression of Hspa5, which encodes the molecular chaperone 78 kDa glucose-regulated protein (GRP78), increased after KA injection in the wild type (WT) mice. Comparative analysis using WT and Atf6 alpha(-/-) mice revealed that MA induced pronounced neuronal death in the CA3 region of Atf6 alpha(-/-) mice. The enhanced neuronal death in Atf6 alpha(-/-) mice was associated with reduced expression of molecular chaperones in the ER and significant induction of c-fos in the hippocampal neurons. Furthermore, an injection of dantrolene, an inhibitor of ryanodine receptor, partially rescued these effects in Atf6 alpha(-/-) mice after KA injection. Our results suggest that ATF6 alpha plays an important role in neuronal survival after KA-induced excitotoxicity through the regulation of Ca2+ response and neuronal activity. (C) 2015 Elsevier Ltd. All rights reserved.