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许琪

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pharmacologic inhibition of hsp90 to prevent glt-1 degradation as an effective therapy for epilepsy

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j exp med,2016,214(2):547–563 | 2016年12月27日 | https://doi.org/10.1084/jem.20160667

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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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