Co-translational protein aggregation after transient cerebral ischemia
Co-translational protein aggregation after transient cerebral ischemia
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DOI：
10.1016/j.neuroscience.2005.05.015
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发表时间：
2005-01-01
期刊：
影响因子：
3.3
通讯作者：
Hu, BR
中科院分区：
文献类型：
--
作者：
Liu, CL;Ge, P;Hu, BR
短暂性脑缺血导致不可逆的翻译抑制，这被认为是缺血后迟发性神经元死亡的标志。本研究利用大鼠短暂性脑缺血模型，探讨不可逆的翻译抑制是否是由于翻译复合物，即核糖体及其相关的新生多肽，起始因子，翻译伴侣和降解酶在缺血后的异常聚集。通过电子显微镜和生化分析研究了平移复合物聚集。持续15或20分钟的脑缺血诱导严重的翻译复合物聚集从30分钟的再灌注开始，并持续到48小时的再灌注延迟性神经元死亡的发病。电子显微镜下，大多数玫瑰花形的多聚核糖体相对均匀地分布在假手术对照神经元的细胞质中。缺血后，大多数核糖体在注定死亡的神经元中聚集成大的异常聚集体。翻译复合物组分包括核糖体小亚基蛋白6、大亚基蛋白28、真核起始因子3 eta、共翻译伴侣热休克同源蛋白70和共翻译伴侣HSP 40-Hdj 1以及共翻译的hsp 70相互作用蛋白的泛素连接酶C末端均在缺血后不可逆地聚集成大的异常蛋白聚集体。翻译组件也高度泛素化。据我们所知，脑缺血后翻译组分的不可逆聚集尚未报道。这项研究清楚地表明，缺血损伤共翻译伴侣和降解机制，导致缺血后蛋白质聚集不可逆地破坏蛋白质合成机制。(c)2005年IRBO。由爱思唯尔有限公司出版。保留所有权利。
Transient cerebral ischemia leads to irreversible translational inhibition which has been considered as a hallmark of delayed neuronal death after ischemia. This study utilized a rat transient cerebral ischemia model to investigate whether irreversible translational inhibition is due to abnormal aggregation of translational complex, i.e. the ribosomes and their associated nascent polypeptides, initiation factors, translational chaperones and degradation enzymes after ischemia. Translational complex aggregation was studied by electron microscopy, as well as by biochemical analyses. A duration of 15 or 20 min of cerebral ischemia induced severe translational complex aggregation starting from 30 min of reperfusion and lasting until the onset of delayed neuronal death at 48 h of reperfusion. Under electron microscopy, most rosette-shaped polyribosomes were relatively evenly distributed in the cytoplasm of sham-operated control neurons. After ischemia, most ribosomes were clumped into large abnormal aggregates in neurons destined to die. Translational complex components consisting of small ribosomal subunit protein 6, large subunit protein 28, eukaryotic initiation factor-3 eta, co-translational chaperone heat shock cognate protein 70 and co-chaperone HSP40-Hdj1, as well as co-translational ubiquitin ligase c-terminus of hsp70-interacting protein were all irreversibly clumped into large abnormal protein aggregates after ischemia. Translational components were also highly ubiquitinated. To our knowledge, irreversible aggregation of translational components has not been reported after brain ischemia. This study clearly indicates that ischemia damages co-translational chaperone and degradation machinery, resulting in irreversible destruction of protein synthesis machinery by protein aggregation after ischemia. (c) 2005 IRBO. Published by Elsevier Ltd. All rights reserved.