ArticleThe Journal of experimental medicine2017
Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy.
Article in The Journal of experimental medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 78 citations in OpenAlex.
- Reblastatin as a neuroprotective agent in temporal lobe epilepsy and excitotoxic conditions of Alzheimer's disease and Parkinson's disease.Acta pharmaceutica Sinica. B · 2026Article
- Targeting Hsp90 with cemdomespib reduces seizure burden and alters disease course in preclinical epilepsy models.Epilepsia · 2026Article
- Modeling epilepsy by loss-of-function of the CUG-binding protein Elav-like family member 2 in zebrafish with multi-omics analysis.Chinese medical journal · 2026Article
- Identification of epileptic hippocampal sclerosis related genes through bulk and single-nucleus RNA sequencing datasets.Cellular and molecular life sciences : CMLS · 2025Article
- Pigment Epithelium-Derived Factor Deficiency Impairs Hippocampal Glutamate Homeostasis and Cognitive Function by Downregulating Astrocytic GLT-1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Pharmacological inhibition of PSPH reduces serine levels and epileptic seizures.Nature chemical biology · 2025Article
- Advances in the structures, mechanisms and targeting of molecular chaperones.Signal transduction and targeted therapy · 2025Review
- Regulation of Glutamate Transporter Type 1 by TSA and the Antiepileptic Mechanism of TSA.Neurochemical research · 2025Article
- The regulatory mechanisms and treatment of HDAC6 in immune dysregulation diseases.Frontiers in immunology · 2025Review
- The Interplay between Glioblastoma Cells and Tumor Microenvironment: New Perspectives for Early Diagnosis and Targeted Cancer Therapy.Brain sciences · 2024Review
- A single-nuclei paired multiomic analysis of the human midbrain reveals age- and Parkinson's disease-associated glial changes.Nature aging · 2024Article
- Role of Necroptosis, a Regulated Cell Death, in Seizure and Epilepsy.Neurochemical research · 2024Review
- HSP90β regulates EAAT2 expression and participates in ischemia‑reperfusion injury in rats.Molecular medicine reports · 2024Article
- The role of molecular chaperones in the mechanisms of epileptogenesis.Cell stress & chaperones · 2023Review
- HSP90β promotes osteoclastogenesis by dual-activation of cholesterol synthesis and NF-κB signaling.Cell death and differentiation · 2023Article
- Astrocytes as a target for therapeutic strategies in epilepsy: current insights.Frontiers in molecular neuroscience · 2023Review
- HAT- and HDAC-Targeted Protein Acetylation in the Occurrence and Treatment of Epilepsy.Biomedicines · 2022Review
- Functional investigation of SLC1A2 variants associated with epilepsy.Cell death & disease · 2022Article
- Pharmacological induction of AMFR increases functional EAAT2 oligomer levels and reduces epileptic seizures in mice.JCI insight · 2022Article
- Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson's disease.Acta neuropathologica · 2022Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.