{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:07:46Z","timestamp":1785150466398,"version":"3.55.0"},"reference-count":72,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T00:00:00Z","timestamp":1713830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ational Institute of Neurological Disease and Stroke (NINDS)","award":["R01 NS082635"],"award-info":[{"award-number":["R01 NS082635"]}]},{"name":"ational Institute of Neurological Disease and Stroke (NINDS)","award":["NS121718"],"award-info":[{"award-number":["NS121718"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A significant number of patients with genetic epilepsy do not obtain seizure freedom, despite developments in new antiseizure drugs, suggesting a need for novel therapeutic approaches. Many genetic epilepsies are associated with misfolded mutant proteins, including GABRG2(Q390X)-associated Dravet syndrome, which we have previously shown to result in intracellular accumulation of mutant GABAA receptor \u03b32(Q390X) subunit protein. Thus, a potentially promising therapeutic approach is modulation of proteostasis, such as increasing endoplasmic reticulum (ER)-associated degradation (ERAD). To that end, we have here identified an ERAD-associated E3 ubiquitin ligase, HRD1, among other ubiquitin ligases, as a strong modulator of wildtype and mutant \u03b32 subunit expression. Overexpressing HRD1 dose-dependently reduced the \u03b32(Q390X) subunit. Additionally, we show that zonisamide (ZNS)\u2014an antiseizure drug reported to upregulate HRD1\u2014reduces seizures in the Gabrg2+\/Q390X mouse. We propose that a possible mechanism for this effect is a partial rescue of surface trafficking of GABAA receptors, which are otherwise sequestered in the ER due to the dominant-negative effect of the \u03b32(Q390X) subunit. Furthermore, this partial rescue was not due to changes in ER chaperones BiP and calnexin, as total expression of these chaperones was unchanged in \u03b32(Q390X) models. Our results here suggest that leveraging the endogenous ERAD pathway may present a potential method to degrade neurotoxic mutant proteins like the \u03b32(Q390X) subunit. We also demonstrate a pharmacological means of regulating proteostasis, as ZNS alters protein trafficking, providing further support for the use of proteostasis regulators for the treatment of genetic epilepsies.<\/jats:p>","DOI":"10.3390\/ijms25094601","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T08:08:27Z","timestamp":1713859707000},"page":"4601","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Modulating Endoplasmic Reticulum Chaperones and Mutant Protein Degradation in GABRG2(Q390X) Associated with Genetic Epilepsy with Febrile Seizures Plus and Dravet Syndrome"],"prefix":"10.3390","volume":"25","author":[{"given":"Sarah","family":"Poliquin","sequence":"first","affiliation":[{"name":"Neuroscience Graduate Program, Vanderbilt University, Nashville, TN 37232, USA"},{"name":"Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6697-0585","authenticated-orcid":false,"given":"Gerald","family":"Nwosu","sequence":"additional","affiliation":[{"name":"Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA"},{"name":"Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA"},{"name":"Department of Neurology, Vanderbilt University Medical Center, 465 21st Ave South, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karishma","family":"Randhave","sequence":"additional","affiliation":[{"name":"Department of Neurology, Vanderbilt University Medical Center, 465 21st Ave South, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangzhen","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Vanderbilt University Medical Center, 465 21st Ave South, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carson","family":"Flamm","sequence":"additional","affiliation":[{"name":"Department of Neurology, Vanderbilt University Medical Center, 465 21st Ave South, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1079-5436","authenticated-orcid":false,"given":"Jing-Qiong","family":"Kang","sequence":"additional","affiliation":[{"name":"Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA"},{"name":"Department of Neurology, Vanderbilt University Medical Center, 465 21st Ave South, Nashville, TN 37232, USA"},{"name":"Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA"},{"name":"Vanderbilt Kennedy Center of Human Development, Vanderbilt University, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/ng0501-49","article-title":"Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures","volume":"28","author":"Wallace","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1093\/brain\/awg018","article-title":"Childhood absence epilepsy and febrile seizures: A family with a GABA(A) receptor mutation","volume":"126","author":"Marini","year":"2003","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1212\/01.wnl.0000230145.73496.a2","article-title":"A novel GABRG2 mutation associated with febrile seizures","volume":"67","author":"Audenaert","year":"2006","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/jhg.2010.47","article-title":"Mutational analysis of GABRG2 in a Japanese cohort with childhood epilepsies","volume":"55","author":"Shi","year":"2010","journal-title":"J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/j.1460-9568.2011.07767.x","article-title":"Novel \u03b11 and \u03b32 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy","volume":"34","author":"Brown","year":"2011","journal-title":"Eur. J. Neurosci."},{"key":"ref_6","unstructured":"Epi4K Consortium, and Epilepsy Phenome\/Genome Project (2017). Ultra-rare genetic variation in common epilepsies: A case-control sequencing study. Lancet Neurol., 16, 135\u2013143."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1080\/01677063.2017.1315417","article-title":"Expanding the phenotypic spectrum of GABRG2 variants: A recurrent GABRG2 missense variant associated with a severe phenotype","volume":"31","author":"Zou","year":"2017","journal-title":"J. Neurogenet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.seizure.2019.03.010","article-title":"Novel variants and phenotypes widen the phenotypic spectrum of GABRG2-related disorders","volume":"69","author":"Schreiber","year":"2019","journal-title":"Seizure"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Saleem, T., Maqbool, H., Sheikh, N., Tayyeb, A., Mukhtar, M., and Ashfaq, A. (2022). GABRG2 C588T Polymorphism Is Associated with Idiopathic Generalized Epilepsy but Not with Antiepileptic Drug Resistance in Pakistani Cohort. BioMed Res. Int., 2022.","DOI":"10.1155\/2022\/3460792"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1111\/epi.17336","article-title":"Molecular and clinical descriptions of patients with GABAA receptor gene variants (GABRA1, GABRB2, GABRB3, GABRG2): A cohort study, review of literature, and genotype-phenotype correlation","volume":"63","author":"Maillard","year":"2022","journal-title":"Epilepsia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"809163","DOI":"10.3389\/fnmol.2022.809163","article-title":"Phenotypic Spectrum and Prognosis of Epilepsy Patients with GABRG2 Variants","volume":"15","author":"Yang","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e35","DOI":"10.1212\/NXG.0000000000000035","article-title":"Novel GABRG2 mutations cause familial febrile seizures","volume":"1","author":"Boillot","year":"2015","journal-title":"Neurol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1007\/s10038-008-0306-y","article-title":"SCN1A, SCN1B, and GABRG2 gene mutation analysis in Chinese families with generalized epilepsy with febrile seizures plus","volume":"53","author":"Sun","year":"2008","journal-title":"J. Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4939","DOI":"10.1007\/s00415-022-11137-4","article-title":"Rare variants in GABRG2 associated with sleep-related hypermotor epilepsy","volume":"269","author":"Jiang","year":"2022","journal-title":"J. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1086\/338710","article-title":"Truncation of the GABAA-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus","volume":"70","author":"Harkin","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1523\/JNEUROSCI.4772-08.2009","article-title":"The GABRG2 mutation, Q351X, associated with generalized epilepsy with febrile seizures plus, has both loss of function and dominant-negative suppression","volume":"29","author":"Kang","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5937","DOI":"10.1523\/JNEUROSCI.5332-11.2012","article-title":"The Intronic GABRG2 Mutation, IVS6+2T\u2192G, Associated with Childhood Absence Epilepsy Altered Subunit mRNA Intron Splicing, Activated Nonsense-Mediated Decay, and Produced a Stable Truncated \u03b32 Subunit","volume":"32","author":"Tian","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1002\/ana.23947","article-title":"Trafficking-deficient mutant GABRG2 subunit amount may modify epilepsy phenotype","volume":"74","author":"Kang","year":"2013","journal-title":"Ann. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.nbd.2013.12.013","article-title":"A Novel GABRG2 Mutation, p.R136*, in a family with GEFS+ and extended phenotypes","volume":"64","author":"Johnston","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.eplepsyres.2013.12.005","article-title":"Association of nonsense mutation in GABRG2 with abnormal trafficking of GABAA receptors in severe epilepsy","volume":"108","author":"Ishii","year":"2014","journal-title":"Epilepsy Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/nn.4024","article-title":"The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration","volume":"18","author":"Kang","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1111\/epi.16670","article-title":"Endoplasmic reticulum stress increases inflammatory cytokines in an epilepsy mouse model Gabrg2+\/Q390X knockin: A link between genetic and acquired epilepsy?","volume":"61","author":"Shen","year":"2020","journal-title":"Epilepsia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.molcel.2004.08.025","article-title":"Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death","volume":"15","author":"Haynes","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41580-020-0250-z","article-title":"Mechanisms, regulation and functions of the unfolded protein response","volume":"21","author":"Hetz","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ghemrawi, R., and Khair, M. (2020). Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176127"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9526","DOI":"10.1074\/jbc.M115.705004","article-title":"Grp94 Protein Delivers \u03b3-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation","volume":"291","author":"Di","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"104754","DOI":"10.1016\/j.isci.2022.104754","article-title":"The endoplasmic reticulum membrane complex promotes proteostasis of GABAA receptors","volume":"25","author":"Whittsette","year":"2022","journal-title":"iScience"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.bcp.2013.06.023","article-title":"Biogenesis, trafficking and up-regulation of nicotinic ACh receptors","volume":"86","author":"Colombo","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nrn2370","article-title":"GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition","volume":"9","author":"Jacob","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_30","unstructured":"Pohl, C., and Dikic, I. (2021, October 07). Cellular Quality Control by the Ubiquitin-Proteasome System and Autophagy. Available online: https:\/\/www.science.org\/doi\/epdf\/10.1126\/science.aax3769."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.neuroscience.2019.12.030","article-title":"Ubiquitination and E3 Ubiquitin Ligases in Rare Neurological Diseases with Comorbid Epilepsy","volume":"428","author":"Zhu","year":"2020","journal-title":"Neuroscience"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3389\/fgene.2018.00029","article-title":"A Comprehensive Atlas of E3 Ubiquitin Ligase Mutations in Neurological Disorders","volume":"9","author":"George","year":"2018","journal-title":"Front. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"768655","DOI":"10.3389\/fncel.2021.768655","article-title":"Exploration of Aberrant E3 Ligases Implicated in Alzheimer\u2019s Disease and Development of Chemical Tools to Modulate Their Function","volume":"15","author":"Potjewyd","year":"2021","journal-title":"Front. Cell Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.3389\/fphys.2020.01022","article-title":"E3 Ubiquitin Ligases in Neurological Diseases: Focus on Gigaxonin and Autophagy","volume":"11","author":"Bomont","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13895","DOI":"10.1523\/JNEUROSCI.2320-10.2010","article-title":"Slow degradation and aggregation in vitro of mutant GABAA receptor gamma2(Q351X) subunits associated with epilepsy","volume":"30","author":"Kang","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3192","DOI":"10.1093\/hmg\/ddw168","article-title":"Differential molecular and behavioural alterations in mouse models of GABRG2 haploinsufficiency versus dominant negative mutations associated with human epilepsy","volume":"25","author":"Warner","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.chembiol.2020.08.012","article-title":"Proteostasis Regulators Restore Function of Epilepsy-Associated GABAA Receptors","volume":"28","author":"Di","year":"2021","journal-title":"Cell Chem. Biol."},{"key":"ref_38","unstructured":"Noebels, J.L., Avoli, M., Rogawski, M.A., Olsen, R.W., and Delgado-Escueta, A.V. (2023, March 02). GABRB3, Epilepsy, and Neurodevelopment, Jasper\u2019s Basic Mechanisms of the Epilepsies [Internet], Available online: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK98178\/."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"18538","DOI":"10.1074\/jbc.M802077200","article-title":"The ubiquitin-like protein Plic-1 enhances the membrane insertion of GABAA receptors by increasing their stability within the endoplasmic reticulum","volume":"283","author":"Saliba","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S1097-2765(00)00040-X","article-title":"The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome","volume":"6","author":"Kleijnen","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1016\/j.celrep.2016.11.067","article-title":"Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation","volume":"17","author":"Delahanty","year":"2016","journal-title":"Cell Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.1093\/hmg\/ddy189","article-title":"Loss of fragile X protein FMRP impairs homeostatic synaptic downscaling through tumor suppressor p53 and ubiquitin E3 ligase Nedd4-2","volume":"27","author":"Lee","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Zhu, J., Lee, K.Y., Jewett, K.A., Man, H.-Y., Chung, H.J., and Tsai, N.-P. (2017). Epilepsy-associated gene Nedd4-2 mediates neuronal activity and seizure susceptibility through AMPA receptors. PLoS Genet., 13.","DOI":"10.1371\/journal.pgen.1006634"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1111\/jnc.13271","article-title":"The tumor suppressor p53 guides GluA1 homeostasis through Nedd4-2 during chronic elevation of neuronal activity","volume":"135","author":"Jewett","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/jnc.14840","article-title":"C2-lacking isoform of Nedd4-2 regulates excitatory synaptic strength through GluA1 ubiquitination-independent mechanisms","volume":"151","author":"Zhu","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"29420","DOI":"10.1074\/jbc.M114.603068","article-title":"Ring finger protein 34 (RNF34) interacts with and promotes \u03b3-aminobutyric acid type-A receptor degradation via ubiquitination of the \u03b32 subunit","volume":"289","author":"Jin","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"16929","DOI":"10.1074\/jbc.M110.215871","article-title":"SEL1L protein critically determines the stability of the HRD1-SEL1L endoplasmic reticulum-associated degradation (ERAD) complex to optimize the degradation kinetics of ERAD substrates","volume":"286","author":"Iida","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1038\/s41401-020-00585-1","article-title":"Zonisamide alleviates cardiac hypertrophy in rats by increasing Hrd1 expression and inhibiting endoplasmic reticulum stress","volume":"42","author":"Wu","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/s41401-020-0461-z","article-title":"Zonisamide, an antiepileptic drug, alleviates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress","volume":"42","author":"Tian","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"192","DOI":"10.3389\/fnagi.2020.00192","article-title":"Zonisamide Ameliorates Cognitive Impairment by Inhibiting ER Stress in a Mouse Model of Type 2 Diabetes Mellitus","volume":"12","author":"He","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s12031-011-9638-8","article-title":"HRD1 levels increased by zonisamide prevented cell death and caspase-3 activation caused by endoplasmic reticulum stress in SH-SY5Y cells","volume":"46","author":"Omura","year":"2012","journal-title":"J. Mol. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.ejphar.2014.09.023","article-title":"Zonisamide suppresses endoplasmic reticulum stress-induced neuronal cell damage in vitro and in vivo","volume":"746","author":"Tsujii","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"239854","DOI":"10.1155\/2013\/239854","article-title":"Endoplasmic reticulum stress and Parkinson\u2019s disease: The role of HRD1 in averting apoptosis in neurodegenerative disease","volume":"2013","author":"Omura","year":"2013","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"fcac144","DOI":"10.1093\/braincomms\/fcac144","article-title":"4-Phenylbutyrate restored \u03b3-aminobutyric acid uptake and reduced seizures in SLC6A1 patient variant-bearing cell and mouse models","volume":"4","author":"Nwosu","year":"2022","journal-title":"Brain Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"37995","DOI":"10.1074\/jbc.M508305200","article-title":"Endoplasmic reticulum retention and associated degradation of a GABAA receptor epilepsy mutation that inserts an aspartate in the M3 transmembrane segment of the alpha1 subunit","volume":"280","author":"Gallagher","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1523\/JNEUROSCI.4512-08.2009","article-title":"Two molecular pathways (NMD and ERAD) contribute to a genetic epilepsy associated with the GABAA receptor GABRA1 PTC mutation, 975delC, S326fs328X","volume":"29","author":"Kang","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/12207","article-title":"Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues","volume":"2","author":"Crestani","year":"1999","journal-title":"Nat. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.euroneuro.2006.06.008","article-title":"Interactions between zonisamide and conventional antiepileptic drugs in the mouse maximal electroshock test model","volume":"17","author":"Borowicz","year":"2007","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.expneurol.2009.11.018","article-title":"The antiepileptic drug zonisamide inhibits MAO-B and attenuates MPTP toxicity in mice: Clinical relevance","volume":"221","author":"Sonsalla","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1097\/wnf.0b013e3180413d7d","article-title":"Clinical pharmacology and mechanism of action of zonisamide","volume":"30","author":"Biton","year":"2007","journal-title":"Clin. Neuropharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.1007\/s00210-023-02538-x","article-title":"Tiagabine and zonisamide differentially regulate the glial properties in an astrocyte-microglia co-culture model of inflammation","volume":"396","author":"Ismail","year":"2023","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Volnova, A., Tsytsarev, V., Ganina, O., V\u00e9lez-Crespo, G.E., Alves, J.M., Ignashchenkova, A., and Inyushin, M. (2022). The Anti-Epileptic Effects of Carbenoxolone In Vitro and In Vivo. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020663"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.1523\/JNEUROSCI.4243-05.2006","article-title":"Why does fever trigger febrile seizures? GABAA receptor gamma2 subunit mutations associated with idiopathic generalized epilepsies have temperature-dependent trafficking deficiencies","volume":"26","author":"Kang","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Mermer, F., Poliquin, S., Zhou, S., Wang, X., Ding, Y., Yin, F., Shen, W., Wang, J., Rigsby, K., and Xu, D. (2022). Astrocytic GABA transporter 1 deficit in novel SLC6A1 variants mediated epilepsy: Connected from protein destabilization to seizures in mice and humans. Neurobiol. Dis., 172.","DOI":"10.1016\/j.nbd.2022.105810"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"20835","DOI":"10.1074\/jbc.M110.200808","article-title":"The endoplasmic reticulum (ER)-associated degradation system regulates aggregation and degradation of mutant neuroserpin","volume":"286","author":"Ying","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ajhg.2018.11.018","article-title":"Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive","volume":"104","author":"Edvardson","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.ajhg.2015.02.016","article-title":"Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures","volume":"96","author":"Carvill","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13041-020-00612-6","article-title":"Endoplasmic reticulum retention and degradation of a mutation in SLC6A1 associated with epilepsy and autism","volume":"13","author":"Wang","year":"2020","journal-title":"Mol. Brain"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/ng.150","article-title":"De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy","volume":"40","author":"Saitsu","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3986","DOI":"10.1038\/s41467-018-06507-4","article-title":"Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones","volume":"9","author":"Guiberson","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.nbd.2018.07.004","article-title":"Reduced axonal surface expression and phosphoinositide sensitivity in Kv7 channels disrupts their function to inhibit neuronal excitability in Kcnq2 epileptic encephalopathy","volume":"118","author":"Kim","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/s41401-023-01172-w","article-title":"Adapting the endoplasmic reticulum proteostasis rescues epilepsy-associated NMDA receptor variants","volume":"45","author":"Zhang","year":"2024","journal-title":"Acta Pharmacol. 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