Loss of the glutamate transporter GLT1 (also known as SLC1A2) occurs in temporal lobe epilepsy (TLE), but the mechanisms mediating GLT1 degradation are not understood. Here, Sha et al. report upregulated expression of HSP90β in reactive astrocytes of human epileptogenic tissue and in mouse models of TLE and febrile seizures. In cultured astrocytes, HSP90β negatively regulated GLT1 protein levels through proteasome-dependent GLT1 degradation, which was prevented by the HSP90 inhibitor, 17AAG. In mouse models of TLE, long-term systemic administration of 17AAG suppressed spontaneous recurrent seizures and ameliorated astrogliosis.
References
Sha, L. et al. Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy. J. Exp. Med. http://dx.doi.org/10.1084/jem.20160667 (2016)
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Crunkhorn, S. HSP90 inhibition suppresses seizures. Nat Rev Drug Discov 16, 88 (2017). https://doi.org/10.1038/nrd.2017.9
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DOI: https://doi.org/10.1038/nrd.2017.9
