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Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy

发布日期:2017/1/23 13:17:02

期刊名称:Journal of Experimental Medicine

期刊号:10.1084/jem.20160667

通迅作者:Xu Qi

作者单位:Chinese Academy of Medical Sciences and Peking Union Medical College

使用产品与服务:siRNA

文章摘要:

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 ofGLT-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 epilepsyInhibition of Hsp90, but not Hsp70, increased GLT-1 levels. Mechanistically, Hsp90β recruits GLT-1 to the 20S proteasome, thereby promoting GLT-1 degradationHsp90 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-1by inhibiting Hsp90β in reactive astrocytes may be a potential therapeutic target for the treatment of epilepsy and excitotoxicity.

实验结果:




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