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

Authors :
Sha, Longze
Wang, Xueqin
Li, Jing
Shi, Xinze
Wu, Liwen
Shen, Yan
Xu, Qi
Source :
The Journal of Experimental Medicine; February 2017, Vol. 214 Issue: 2 p547-563, 17p
Publication Year :
2017

Abstract

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.

Details

Language :
English
ISSN :
00221007 and 15409538
Volume :
214
Issue :
2
Database :
Supplemental Index
Journal :
The Journal of Experimental Medicine
Publication Type :
Periodical
Accession number :
ejs41266257
Full Text :
https://doi.org/10.1084/jem.20160667