导读：  许琪课题组在”J Exp Med” 杂志发表研究论文“Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy（2017）”。2017年2月的Nature Reviews Drug Discovery杂志在线版上，以“研究亮点”的形式报道了本研究成果，指出该研究发现了GLT-1“缺失”的分子机制，靶向Hsp90的抑制剂或新型治疗方法具有做为治疗颞叶癫痫的潜质（题目：HSP90 inhibition suppresses seizures，链接：http://www.nature.com/nrd/journal/v16/n2/full/nrd.2017.9.html）。颞叶癫痫是一类最常见的难治性癫痫，而星形胶质细胞GLT1蛋白的缺失会导致其谷氨酸调节功能紊乱，造成胞外谷氨酸累积和癫痫发作。本研究旨在鉴别GLT1蛋白缺失的分子机制，并研究靶向抑制GLT1蛋白的缺失机制是否具有抗癫痫效果。

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       中国医学科学院基础医学研究所，“医学分子生物学国家重点实验室”的许琪研究团队通过研究发现，Hsp90β亚型在颞叶癫痫患者和癫痫模型小鼠致癫灶的星形胶质细胞中表达升高。抑制Hsp90活性可以提高GLT1的蛋白水平。分子机制方面，Hsp90β可以将GLT1募集至20S蛋白酶体从而促进GLT1的降解。Hsp90抑制剂通过打断Hsp90β与GLT1之间的相互作用从而稳定GLT1的蛋白水平。通过利用颞叶癫痫模型小鼠，本研究证实了一种Hsp90抑制剂——17AAG能够有效抑制慢性自发性癫痫发作，并缓解星形胶质细胞增生的病理表现。综上所述，本研究阐明了一种GLT1异常降解的分子机制，并为治疗癫痫和神经兴奋性毒性提供新的分子靶标。

       【摘要】： The glutamate transporter GLT-1 is critical for the maintenance of low interstitial glutamate concentrations. Loss of GLT-1 is commonly observed in neurological disorders, including temporal lobe epilepsy (TLE). Despite the hypothesis that targeting the mechanisms of GLT-1 deficiency may be a novel strategy for treating drug-resistant epilepsy, the underlying molecular cascade remains largely unknown. Here, we show that Hsp90β is up-regulated in reactive astrocytes of the epileptic hippocampus in patients with TLE and mouse models of epilepsy. Inhibition of Hsp90, but not Hsp70, increased GLT-1 levels. Mechanistically, Hsp90β recruits GLT-1 to the 20S proteasome, thereby promoting GLT-1 degradation. Hsp90 inhibitor prevents GLT-1 degradation by disrupting the association between Hsp90β and GLT-1. Using a model of TLE, we demonstrated that long-term systemic administration of 17AAG dramatically suppressed spontaneous recurrent seizures and ameliorated astrogliosis. Overall, these results suggest that up-regulation of GLT-1 by inhibiting Hsp90β in reactive astrocytes may be a potential therapeutic target for the treatment of epilepsy and excitotoxicity.

       相关结果已发表于”J Exp Med.” 2017, 214(2)，本文通讯作者为许琪研究员，第一作者为课题组助理研究员沙龙泽。该研究工作得到了以下基金的支持：973计划（2013CB531301）；国家自然科学基金（81501131,81471325,31430048,81625008）；北京市科学技术委员会（Z151100003915119）；协和青年基金（3332016134）；中国医学科学院医学与健康科技创新工程（2016-I2M-1-004）。

转载评述：NATURE REVIEWS DRUG DISCOVERY | RESEARCH HIGHLIGHT

EPILEPSY：HSP90 inhibition suppresses seizures

By: Sarah Crunkhorn

From: Nature Reviews Drug Discovery 16, 88 (2017)

Date: Published online 02 February 2017

Subject terms: Drug discovery

       Loss of the glutamate transporter GLT1 (also known as SLC1A2) occurs in temporal lobe epilepsy (TLE), but the mechanisms mediating GLT1 degradation are not understood. Here, Sha et al. report upregulated expression of HSP90β in reactive astrocytes of human epileptogenic tissue and in mouse models of TLE and febrile seizures. In cultured astrocytes, HSP90β negatively regulated GLT1 protein levels through proteasome-dependent GLT1 degradation, which was prevented by the HSP90 inhibitor, 17AAG. In mouse models of TLE, long-term systemic administration of 17AAG suppressed spontaneous recurrent seizures and ameliorated astrogliosis.

医学分子生物学国家重点实验室