Targeting Hsp90/Hsp70-based protein quality control for treatment of adult onset neurodegenerative diseases.
Targeting Hsp90/Hsp70-based protein quality control for treatment of adult onset neurodegenerative diseases.
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DOI：
10.1146/annurev-pharmtox-010814-124332
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发表时间：
2015
影响因子：
12.5
通讯作者：
Lieberman AP
中科院分区：
文献类型：
--
作者：
Pratt WB;Gestwicki JE;Osawa Y;Lieberman AP
目前可用于成人起病的神经退行性疾病的治疗方法提供了症状缓解，但不能改变疾病。在这里，我们探索了一种新的神经保护方法，该方法基于以伴侣为靶点的药物指导的蛋白质质量控制。在这些疾病中展开和聚集的关键靶蛋白，如多聚谷氨酰胺雄激素受体(脊髓和球部肌肉萎缩)、亨廷顿蛋白(亨廷顿病)、α-突触核蛋白(帕金森病)和tau(阿尔茨海默病)是热休克蛋白90的客户蛋白，它们的周转受到基于热休克蛋白90/热休克蛋白70的伴侣机制的蛋白质质量控制功能的调节。在蛋白质质量控制中，Hsp90和Hsp70对客户蛋白的稳定性有相反的影响；Hsp90稳定客户并抑制其泛素化，而Hsp70促进依赖芯片的泛素化和蛋白酶体降解。我们讨论了通过抑制Hsp90功能或促进Hsp70功能来调节蛋白平衡的药物如何在细胞和动物疾病模型中促进关键聚集蛋白的降解和改善中毒症状。
Currently available therapies for adult onset neurodegenerative diseases provide symptomatic relief, but are not disease modifying. We explore here a new neuroprotective approach based on drugs targeting chaperone-directed protein quality control. Critical target proteins that unfold and aggregate in these diseases, such as the polylglutamine androgen receptor (spinal and bulbar muscular atrophy), huntingtin (Huntington’s disease), α-synuclein (Parkinson’s disease) and tau (Alzheimer’s disease) are client proteins of Hsp90, and their turnover is regulated by the protein quality control function of the Hsp90/Hsp70-based chaperone machinery. In protein quality control Hsp90 and Hsp70 have opposing effects on client protein stability; Hsp90 stabilizes the clients and inhibits their ubiquitination, whereas Hsp70 promotes CHIP-dependent ubiquitination and proteasomal degradation. We discuss how drugs that modulate proteostasis by inhibiting Hsp90 function or by promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models.
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影响因子：
14.5
作者：
Adachi, H;Katsuno, M;Sobue, G
通讯作者：
Sobue, G
影响因子：
4.8
作者：
Baldo, Barbara;Weiss, Andreas;Kaupmann, Klemens
通讯作者：
Kaupmann, Klemens
影响因子：
4.8
作者：
Auluck, PK;Meulener, MC;Bonini, NM
通讯作者：
Bonini, NM
影响因子：
21.3
作者：
Connell, P;Ballinger, CA;Patterson, C
通讯作者：
Patterson, C
DOI：
10.1073/pnas.242720499
发表时间：
2003-01-21
影响因子：
11.1
作者：
Dou, F;Netzer, WJ;Xu, HX
通讯作者：
Xu, HX