Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy
Open Access
- 27 December 2016
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 214 (2), 547-563
- https://doi.org/10.1084/jem.20160667
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.Funding Information
- National Natural Science Foundation of China (81501131, 81471325, 31430048, 81625008)
- Beijing Municipal Science and Technology Commission (Z151100003915119)
This publication has 50 references indexed in Scilit:
- Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trialThe Lancet Neurology, 2014
- Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotectionJCI Insight, 2014
- Protein Kinase C (PKC)-promoted Endocytosis of Glutamate Transporter GLT-1 Requires Ubiquitin Ligase Nedd4-2-dependent Ubiquitination but Not PhosphorylationOnline Journal of Public Health Informatics, 2012
- An In Vitro Model of Reactive Astrogliosis and Its Effect on Neuronal GrowthMethods in molecular biology (Clifton, N.J.), 2011
- The influence of epileptic neuropathology and prior peripheral immunity on CNS transduction by rAAV2 and rAAV5Gene Therapy, 2011
- Heat shock protein 90 in neurodegenerative diseasesMolecular Neurodegeneration, 2010
- HSP90 and the chaperoning of cancerNature Reviews Cancer, 2005
- 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degenerationNature Medicine, 2005
- Hsp90 Inhibitor Geldanamycin and Its Derivatives as Novel Cancer Chemotherapeutic AgentsCurrent Pharmaceutical Design, 2005
- Na+ dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) in primary astrocyte cultures: effect of oxidative stressBrain Research, 2001