| First Author | Sha L | Year | 2017 |
| Journal | J Exp Med | Volume | 214 |
| Issue | 2 | Pages | 547-563 |
| PubMed ID | 28028152 | Mgi Jnum | J:240102 |
| Mgi Id | MGI:5882430 | Doi | 10.1084/jem.20160667 |
| Citation | Sha L, et al. (2017) Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy. J Exp Med 214(2):547-563 |
| abstractText | 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 Hsp90beta 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, Hsp90beta recruits GLT-1 to the 20S proteasome, thereby promoting GLT-1 degradation. Hsp90 inhibitor prevents GLT-1 degradation by disrupting the association between Hsp90beta 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 Hsp90beta in reactive astrocytes may be a potential therapeutic target for the treatment of epilepsy and excitotoxicity. |
