17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration
17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration
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DOI：
10.1038/nm1298
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发表时间：
2005-10-01
期刊：
影响因子：
82.9
通讯作者：
Sobue, G
中科院分区：
文献类型：
--
作者：
Waza, M;Adachi, H;Sobue, G
热休克蛋白90（Hsp 90）作为多分子伴侣复合物的一部分发挥作用，该复合物折叠、激活和组装其客户蛋白。雄激素受体（AR）是Hsp 90的客户蛋白之一，是脊髓延髓肌萎缩症（SBMA）的致病基因产物。我们研究了17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG），一种有效的热休克蛋白90抑制剂的治疗效果，以及其降解聚谷氨酰胺扩增的突变体AR的能力。通过减少单体和聚集的突变体AR的量，17-AAG的给药显著改善了SBMA转基因小鼠模型中的运动障碍，而没有可检测到的毒性。与野生型AR相比，突变型AR对Hsp 90-p23表现出更高的亲和力，并优先形成Hsp 90分子伴侣复合物;与野生型AR相比，在细胞和转基因小鼠中，突变型AR在17-AAG存在下优先降解。17-AAG还轻度诱导Hsp 70和Hsp 40。17-因此，AAG将提供一个新的治疗方法SBMA和可能的其他相关的神经退行性疾病。
Heat-shock protein 90 (Hsp90) functions as part of a multichaperone complex that folds, activates and assembles its client proteins. Androgen receptor (AR), a pathogenic gene product in spinal and bulbar muscular atrophy (SBMA), is one of the Hsp90 client proteins. We examined the therapeutic effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a potent Hsp90 inhibitor, and its ability to degrade polyglutamine-expanded mutant AR. Administration of 17-AAG markedly ameliorated motor impairments in the SBMA transgenic mouse model without detectable toxicity, by reducing amounts of monomeric and aggregated mutant AR. The mutant AR showed a higher affinity for Hsp90-p23 and preferentially formed an Hsp90 chaperone complex as compared to wild-type AR; mutant AR was preferentially degraded in the presence of 17-AAG in both cells and transgenic mice as compared to wild-type AR. 17-AAG also mildly induced Hsp70 and Hsp40. 17-AAG would thus provide a new therapeutic approach to SBMA and probably to other related neurodegenerative diseases.