Ethanol induces endoplasmic reticulum stress in the developing brain.
Ethanol induces endoplasmic reticulum stress in the developing brain.
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DOI：
10.1111/j.1530-0277.2011.01503.x
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发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
Luo J
中科院分区：
文献类型：
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作者：
Ke Z;Wang X;Liu Y;Fan Z;Chen G;Xu M;Bower KA;Frank JA;Li M;Fang S;Shi X;Luo J
大脑发育过程中的乙醇暴露会对中枢神经系统（CNS）造成严重损害。潜在的细胞/分子机制仍不清楚。内质网（ER）参与翻译后蛋白质的加工和转运。未折叠或错误折叠的蛋白质在ER腔中的积累触发ER应激，其特征在于翻译衰减、ER伴侣蛋白的合成和转录因子的激活。持续的内质网应激最终导致细胞死亡。ER应激与各种神经退行性过程有关。使用晚期妊娠等效的乙醇暴露小鼠模型，我们测试的假设，乙醇诱导ER应激在发育中的大脑。7日龄C57 BL/6小鼠通过皮下注射急性暴露于乙醇，并检测ER应激诱导蛋白（ERSIPs）的表达和与ER应激相关的信号通路。乙醇暴露显著增加了ERSIP的表达，并激活了与ER应激相关的信号通路;这些通路包括ATF 6、CHOP/GADD 153、GRP 78和中脑星形胶质细胞源性神经营养因子，以及IRE 1 α、eIF 2 α、PERK和PKR的磷酸化。乙醇诱导的ERSIPs增加发生在乙醇注射后4小时内，并且一些ERSIPs的水平在乙醇暴露24小时后仍然升高。乙醇诱导的磷酸化eIF 2 α、caspase-12和CHOP的增加分布在大脑皮质、海马和丘脑的特定区域的神经元中。我们的研究结果表明，乙醇诱导未成熟神经元的内质网应激，提供了新的见解乙醇的有害影响的发展中的中枢神经系统。
Ethanol exposure during brain development causes profound damages to the central nervous system (CNS). The underlying cellular/molecular mechanisms remain unclear. The endoplasmic reticulum (ER) is involved in posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress, which is characterized by translational attenuation, synthesis of ER chaperone proteins, and activation of transcription factors. Sustained ER stress ultimately leads to cell death. ER stress is implicated in various neurodegenerative processes. Using a third trimester equivalent mouse model of ethanol exposure, we tested the hypothesis that ethanol induces ER stress in the developing brain. Seven-day-old C57BL/6 mice were acutely exposed to ethanol by subcutaneous injection and the expression of ER stress-inducible proteins (ERSIPs) and signaling pathways associated with ER stress were examined. Ethanol exposure significantly increased the expression of ERSIPs and activated signaling pathways associated with ER stress; these include ATF6, CHOP/GADD153, GRP78, and mesencephalic astrocyte-derived neurotrophic factor as well as the phosphorylation of IRE1α, eIF2α, PERK, and PKR. The ethanol-induced increase in ERSIPs occurred within 4 hours of ethanol injection, and levels of some ERSIPs remained elevated after 24 hours of ethanol exposure. Ethanol-induced increase in phosphorylated eIF2α, caspase-12, and CHOP was distributed in neurons of specific areas of the cerebral cortex, hippocampus, and thalamus. Our finding indicates that ethanol induces ER stress in immature neurons, providing novel insight into ethanol’s detrimental effect on the developing CNS.