17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse
17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse
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DOI：
10.1093/hmg/ddn419
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发表时间：
2009-03-01
影响因子：
3.5
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Tokui, Keisuke;Adachi, Hiroaki;Sobue, Gen
泛素-蛋白酶体系统（UPS）是主要的蛋白质降解系统，其标记并靶向短寿命蛋白质以及受损或错误折叠的蛋白质以进行破坏。在脊髓延髓肌萎缩症（SBMA）中，雄激素受体（AR），一种Hsp 90客户蛋白，是这样一种错误折叠的蛋白质，倾向于在神经元中聚集。Hsp 90抑制剂通过UPS促进Hsp 90客户蛋白的降解。在SBMA转基因小鼠模型中，我们研究了功能性UPS是否被保留，是否能够降解聚谷氨酰胺扩增的突变AR，以及口服Hsp 90抑制剂17-（二甲氨基乙氨基）-17-去甲氧基格尔德霉素（17-DMAG）的治疗效果。泛素-蛋白酶体功能在SBMA小鼠中得到很好的保留，甚至在小鼠发展严重表型的晚期阶段增加。给药17-DMAG可显著改善SBMA小鼠的运动障碍，且无可检测的毒性，单体和核累积突变AR的量也减少。与野生型AR相比，突变型AR在SBMA细胞和小鼠模型中17-DMAG存在下优先降解。17-DMAG还显著诱导Hsp 70和Hsp 40。因此，17-DMAG将通过保留蛋白酶体功能对SBMA发挥治疗作用。
The ubiquitin-proteasome system (UPS) is the principal protein degradation system that tags and targets short-lived proteins, as well as damaged or misfolded proteins, for destruction. In spinal and bulbar muscular atrophy (SBMA), the androgen receptor (AR), an Hsp90 client protein, is such a misfolded protein that tends to aggregate in neurons. Hsp90 inhibitors promote the degradation of Hsp90 client proteins via the UPS. In a transgenic mouse model of SBMA, we examined whether a functioning UPS is preserved, if it was capable of degrading polyglutamine-expanded mutant AR, and what might be the therapeutic effects of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), an oral Hsp90 inhibitor. Ubiquitin-proteasomal function was well preserved in SBMA mice and was even increased during advanced stages when the mice developed severe phenotypes. Administration of 17-DMAG markedly ameliorated motor impairments in SBMA mice without detectable toxicity and reduced amounts of monomeric and nuclear-accumulated mutant AR. Mutant AR was preferentially degraded in the presence of 17-DMAG in both SBMA cell and mouse models when compared with wild-type AR. 17-DMAG also significantly induced Hsp70 and Hsp40. Thus, 17-DMAG would exert a therapeutic effect on SBMA via preserved proteasome function.