Pharmacological tuning of heat shock protein 70 modulates polyglutamine toxicity and aggregation.
Pharmacological tuning of heat shock protein 70 modulates polyglutamine toxicity and aggregation.
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DOI：
10.1021/cb300166p
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发表时间：
2012-09-21
影响因子：
4
通讯作者：
Duennwald, Martin L.
中科院分区：
文献类型：
--
作者：
Chafekar, Sidhartha M.;Wisen, Susanne;Thompson, Andrea D.;Echeverria, AnaLisa;Walter, Gladis M.;Evans, Christopher G.;Makley, Leah N.;Gestwicki, Jason E.;Duennwald, Martin L.
九种神经退行性疾病是由不同蛋白质内多聚谷氨酰胺（polyQ）区域的异常扩张引起的。遗传和生物化学证据已经证明，分子伴侣热休克蛋白70（Hsp70），调节polyQ毒性和聚集，但目前仍不清楚如何热休克蛋白70可能被用作polyQ相关疾病的潜在目标。我们已经利用了一对膜渗透性化合物，通过刺激或抑制其ATP酶功能来调节Hsp70的活性。在polyQ聚集和毒性的酵母和PC12细胞模型中使用这两种药理学试剂，我们惊讶地发现刺激Hsp70溶解了polyQ构象异构体，同时加剧了polyQ介导的毒性。相比之下，抑制Hsp70的ATP酶活性保护免受polyQ毒性并促进聚集。这些发现阐明了Hsp70作为polyQ疾病中可能的药物靶点的作用，并表明Hsp70使用ATP水解来帮助将polyQ蛋白质划分为具有不同蛋白毒性水平的结构。因此，我们的研究结果支持一个新兴的概念，其中某些种类的polyQ聚集体可能是保护性的，而更可溶的polyQ种类是有毒的。
Nine neurodegenerative disorders are caused by the abnormal expansion of polyglutamine (polyQ) regions within distinct proteins. Genetic and biochemical evidence has documented that the molecular chaperone, heat shock protein 70 (Hsp70), modulates polyQ toxicity and aggregation, yet it remains unclear how Hsp70 might be used as a potential target in polyQ-related diseases. We have utilized a pair of membrane-permeable compounds that tune the activity of Hsp70 by either stimulating or by inhibiting its ATPase functions. Using these two pharmacological agents in both yeast and PC12 cell models of polyQ aggregation and toxicity, we were surprised to find that stimulating Hsp70 solubilized polyQ conformers and simultaneously exacerbated polyQ-mediated toxicity. By contrast, inhibiting Hsp70’s ATPase activity protected against polyQ toxicity and promoted aggregation. These findings clarify Hsp70’s role as a possible drug target in polyQ disorders and suggest that Hsp70 uses ATP hydrolysis to help partition polyQ proteins into structures with varying levels of proteotoxicity. Our results thus support an emerging concept in which certain kinds of polyQ aggregates may be protective, while more soluble polyQ species are toxic.
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影响因子：
10.5
作者：
Duennwald, Martin L.;Lindquist, Susan
通讯作者：
Lindquist, Susan
影响因子：
64.5
作者：
HARSHMAN, KD;MOYEROWLEY, WS;PARKER, CS
通讯作者：
PARKER, CS
影响因子：
14.8
作者：
Calamini, Barbara;Silva, Maria Catarina;Madoux, Franck;Hutt, Darren M.;Khanna, Shilpi;Chalfant, Monica A.;Saldanha, S. Adrian;Hodder, Peter;Tait, Bradley D.;Garza, Dan;Balch, William E.;Morimoto, Richard I.
通讯作者：
Morimoto, Richard I.
影响因子：
4.9
作者：
Evans, Christopher G.;Jinwal, Umesh K.;Gestwicki, Jason E.
通讯作者：
Gestwicki, Jason E.
影响因子：
5.2
作者：
Evans CG;Gestwicki JE
通讯作者：
Gestwicki JE