Protein aggregation and proteasome dysfunction after brain ischemia
Protein aggregation and proteasome dysfunction after brain ischemia
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DOI：
10.1161/strokeaha.107.487108
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发表时间：
2007-12-01
期刊：
影响因子：
8.3
通讯作者：
Hu, Bingren
中科院分区：
文献类型：
--
作者：
Ge, Pengfei;Luo, Yinan;Hu, Bingren
背景和目的-蛋白质解折叠和聚集是脑缺血后神经元的主要早期致病事件。本研究采用短暂性脑缺血模型，探讨脑缺血后未折叠蛋白的过度产生是否是蛋白酶体功能障碍的结果。方法-蛋白酶体肽酶活性测定，蛋白质印迹分析，和尺寸排阻色谱法研究蛋白酶体肽酶活性和蛋白酶体亚细胞再分布和组装。结果-蛋白酶体肽酶活性，如用肽底物琥珀酰-LLVY-7-氨基-4-甲基香豆素测定的，在短暂脑缺血后再灌注的早期，26 S蛋白酶体被适度降低，并且26 S蛋白酶体被分解。此外，蛋白酶体亚基，特别是19 S组分，沉积到蛋白质聚集体含有馏分后，短暂性脑ischemia. Conclusions，这些结果清楚地表明，脑缺血发作后，蛋白酶体被拆卸和聚集，从而无法正常工作。蛋白酶体沉积成蛋白质聚集体也可能表明蛋白酶体试图降解脑缺血后过度产生的泛素缀合蛋白（泛素）。然而，泛蛋白太多而不能被降解，并且在脑缺血后将一些蛋白酶体捕获到它们的聚集体中。
Background and Purpose-Protein unfolding and aggregation are dominant early pathogenic events in neurons after brain ischemia. This study used a transient cerebral ischemia model to investigate whether overproduction of unfolded proteins after brain ischemia is a consequence of proteasome dysfunction.Methods-Proteasome peptidase activity and proteasome subcellular redistribution and assembly were studied by peptidase activity assay, Western blot analysis, and size-exclusion chromatography.Results-Proteasome peptidase activity, as determined with the peptide substrate succinyl-LLVY-7-amino-4-methylcoumarin, was moderately decreased, and the 26S proteasome was disassembled during the early period of reperfusion after transient brain ischemia. Furthermore, the proteasome subunits, particularly the 19S components, were deposited into the protein aggregate-containing fraction after an episode of transient cerebral ischemia.Conclusions-These results clearly demonstrate that after an episode of brain ischemia, proteasomes are disassembled and aggregated and thus fail to function normally. Deposition of proteasomes into protein aggregates may also indicate that proteasomes attempt to degrade ubiquitin-conjugated proteins (ubiproteins) overproduced after brain ischemia. However, ubiproteins are too numerous to be degraded and trap some of the proteasomes into their aggregates after brain ischemia.