Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy.
Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy.
复制标题
Hsp90 的药理抑制可防止 GLT-1 降解，作为癫痫的有效治疗方法
DOI：
10.1084/jem.20160667
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发表时间：
2017-02
期刊：
影响因子：
--
通讯作者：
Xu Q
中科院分区：
文献类型：
--
作者：
Sha L;Wang X;Li J;Shi X;Wu L;Shen Y;Xu Q
谷氨酸转运蛋白GLT-1对于维持低间质谷氨酸浓度至关重要。GLT-1的缺失通常在神经系统疾病中观察到，包括颞叶癫痫（TLE）。尽管假设靶向GLT-1缺陷的机制可能是治疗耐药性癫痫的新策略，但潜在的分子级联仍然在很大程度上未知。在这里，我们表明，热休克蛋白90上调癫痫患者和癫痫小鼠模型的癫痫海马反应性星形胶质细胞。抑制Hsp 90而非Hsp 70可增加GLT-1水平。从机制上讲，Hsp 90将GLT-1募集到20 S蛋白酶体，从而促进GLT-1降解。Hsp 90抑制剂通过破坏Hsp 90和GLT-1之间的结合来防止GLT-1降解。使用TLE模型，我们证明了17 AAG的长期全身给药显著抑制自发性复发性癫痫发作并改善星形胶质细胞增生。总之，这些结果表明，通过抑制反应性星形胶质细胞中的Hsp 90上调GLT-1可能是治疗癫痫和兴奋性毒性的潜在治疗靶点。
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 Hsp90&bgr; 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, Hsp90&bgr; recruits GLT-1 to the 20S proteasome, thereby promoting GLT-1 degradation. Hsp90 inhibitor prevents GLT-1 degradation by disrupting the association between Hsp90&bgr; 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 Hsp90&bgr; in reactive astrocytes may be a potential therapeutic target for the treatment of epilepsy and excitotoxicity.