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

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...

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Autores principales: Sha, Longze, Wang, Xueqin, Li, Jing, Shi, Xinze, Wu, Liwen, Shen, Yan, Xu, Qi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294855/
https://www.ncbi.nlm.nih.gov/pubmed/28028152
http://dx.doi.org/10.1084/jem.20160667
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author Sha, Longze
Wang, Xueqin
Li, Jing
Shi, Xinze
Wu, Liwen
Shen, Yan
Xu, Qi
author_facet Sha, Longze
Wang, Xueqin
Li, Jing
Shi, Xinze
Wu, Liwen
Shen, Yan
Xu, Qi
author_sort Sha, Longze
collection PubMed
description 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.
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spelling pubmed-52948552017-08-01 Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy Sha, Longze Wang, Xueqin Li, Jing Shi, Xinze Wu, Liwen Shen, Yan Xu, Qi J Exp Med Research Articles 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. The Rockefeller University Press 2017-02 /pmc/articles/PMC5294855/ /pubmed/28028152 http://dx.doi.org/10.1084/jem.20160667 Text en © 2017 Sha et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Sha, Longze
Wang, Xueqin
Li, Jing
Shi, Xinze
Wu, Liwen
Shen, Yan
Xu, Qi
Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy
title Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy
title_full Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy
title_fullStr Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy
title_full_unstemmed Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy
title_short Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy
title_sort pharmacologic inhibition of hsp90 to prevent glt-1 degradation as an effective therapy for epilepsy
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294855/
https://www.ncbi.nlm.nih.gov/pubmed/28028152
http://dx.doi.org/10.1084/jem.20160667
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