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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Amyloid precursor protein accumulates in aggresomes in response to proteasome inhibitor
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Amyloid precursor protein accumulates in aggresomes in response to proteasome inhibitor

机译：淀粉样前体蛋白对蛋白酶体抑制剂的反应聚集在聚集体中

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摘要

Aggresomes are cytoplasmic inclusions which are localized at the microtubule organizing center (MTOC) as a result of induced proteasome inhibition, stress or over-expression of certain proteins. Aggresomes are linked to the pathogenesis of many neurodegenerative diseases. Here we studied whether amyloid precursor protein (APP), a type-I transmembrane glycoprotein, is localized in aggresomes after exposure to stress condition. Using confocal microscopy we found that APP is located in aggresomes and co-localized with vimentin, γ-tubulin, 20S and ubiquitin at the MTOC in response to proteasome dysfunction. An interaction between vimentin and APP was found after proteasome inhibition suggesting that APP is an additional protein constituent of aggresomes. Suppression of the proteasome system in APP-HEK293 cells overexpressing APP or transfected with APP Swedish mutation caused an accumulation of stable, detergent-insoluble forms of APP containing poly-ubiquitinated proteins. In addition, brain homogenates from transgenic mice expressing human APP with the Arctic mutation demonstrated an interaction between APP and the aggresomal-marker vimentin. These data suggest that malfunctioning of the proteasome system caused by mutation or overexpression of pathological or non-pathological proteins may lead to the accumulation of stable aggresomes, perhaps contributing to the neurodegeneration.
机译：脂质体是胞质内含物，由于诱导的蛋白酶体抑制，某些蛋白质的应激或过表达，它们位于微管组织中心（MTOC）。聚集蛋白与许多神经退行性疾病的发病机理有关。在这里，我们研究了淀粉样前体蛋白（APP），一种I型跨膜糖蛋白，在暴露于应激条件后是否位于聚集体中。使用共聚焦显微镜，我们发现APP位于蛋白酶体中，并与波形蛋白，γ-微管蛋白，20S和泛素共同定位在MTOC上，以响应蛋白酶体功能障碍。蛋白酶体抑制后发现波形蛋白和APP之间有相互作用，这表明APP是聚集体的另一种蛋白质成分。过表达APP或用APP瑞典突变转染的APP-HEK293细胞中蛋白酶体系统的抑制导致含有多泛素化蛋白的APP的稳定，去污剂不溶形式的积累。此外，来自表达具有北极突变的人APP的转基因小鼠的脑匀浆显示APP与总蛋白标记波形蛋白之间存在相互作用。这些数据表明，由病理或非病理蛋白质的突变或过表达引起的蛋白酶体系统功能异常可能导致稳定的聚集体积累，可能导致神经变性。

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