title: Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy.
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.
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Longze
authors.identifier: 0000-0001-7372-6644
authors.initials: L
authors.lastname: Sha
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Xueqin
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Xinze
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
authors.forename: Liwen
authors.initials: L
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Yan
authors.identifier: 0000-0002-4845-6037
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China xuqi@pumc.edu.cn.
authors.forename: Qi
authors.identifier: 0000-0003-2660-8092
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology; D002478:Cells, Cultured; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000032:analysis / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D003294:Seizures, Febrile / Q000188:drug therapy / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D027342:Excitatory Amino Acid Transporter 2; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018696:Neuroprotective Agents; C493396:Slc1a2 protein, mouse; D018698:Glutamic Acid; C112765:tanespimycin; D046988:Proteasome Endopeptidase Complex