Rapamycin inhibits polyglutamine aggregation independently of autophagy by reducing protein synthesis
Rapamycin inhibits polyglutamine aggregation independently of autophagy by reducing protein synthesis
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DOI：
10.1124/mol.107.043398
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发表时间：
2008-04-01
影响因子：
3.6
通讯作者：
Wyttenbach, Andreas
中科院分区：
文献类型：
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作者：
King, Matthew A.;Hands, Sarah;Wyttenbach, Andreas
错误折叠蛋白质和蛋白质组装体的积累与阿尔茨海默病、帕金森病和亨廷顿病 (HD) 等多种神经退行性疾病中的神经元功能障碍和死亡有关。因此，了解作用于调节错误折叠和/或聚集途径的药物的分子机制至关重要。值得注意的是，雷帕霉素抑制剂雷帕霉素或其类似物的哺乳动物靶点已被提议作为有前途的治疗化合物，通过激活自噬来清除这些疾病中的有毒蛋白组装体。然而，使用 HD 细胞模型，我们发现雷帕霉素可显着降低自噬良好和自噬缺陷细胞中易于聚集的聚谷氨酰胺 (polyQ) 并扩大亨廷顿蛋白及其包涵体 (IB)（通过基因敲除小鼠胚胎成纤维细胞中的 atg5 基因）。这一结果表明雷帕霉素通过自噬以外的途径调节错误折叠的polyQ蛋白的水平。我们发现雷帕霉素通过适度抑制蛋白质合成来减少可溶性 PolyQ 蛋白的量，从而显着减少不溶性 PolyQ 蛋白的形成和 IB 的形成。因此，雷帕霉素对亨廷顿蛋白合成的适度减少可能会导致达到成核事件和随后的有毒聚Q聚集所需的临界浓度的概率大幅降低。因此，除了之前提出的通过自噬途径减少polyQ聚集/毒性的有益作用外，雷帕霉素还可以通过其对整体蛋白质合成的影响来减轻polyQ疾病病理。这一发现可能具有重要的治疗意义。
Accumulation of misfolded proteins and protein assemblies is associated with neuronal dysfunction and death in several neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease (HD). It is therefore critical to understand the molecular mechanisms of drugs that act on pathways that modulate misfolding and/or aggregation. It is noteworthy that the mammalian target of rapamycin inhibitor rapamycin or its analogs have been proposed as promising therapeutic compounds clearing toxic protein assemblies in these diseases via activation of autophagy. However, using a cellular model of HD, we found that rapamycin significantly decreased aggregation-prone polyglutamine (polyQ) and expanded huntingtin and its inclusion bodies (IB) in both autophagy-proficient and autophagy-deficient cells (by genetic knockout of the atg5 gene in mouse embryonic fibroblasts). This result suggests that rapamycin modulates the levels of misfolded polyQ proteins via pathways other than autophagy. We show that rapamycin reduces the amount of soluble polyQ protein via a modest inhibition of protein synthesis that in turn significantly reduces the formation of insoluble polyQ protein and IB formation. Hence, a modest reduction in huntingtin synthesis by rapamycin may lead to a substantial decrease in the probability of reaching the critical concentration required for a nucleation event and subsequent toxic polyQ aggregation. Thus, in addition to its beneficial effect proposed previously of reducing polyQ aggregation/toxicity via autophagic pathways, rapamycin may alleviate polyQ disease pathology via its effect on global protein synthesis. This finding may have important therapeutic implications.