title: The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration.
abstract: Genetic epilepsy and neurodegenerative diseases are two common neurological disorders that are conventionally viewed as being unrelated. A subset of patients with severe genetic epilepsies who have impaired development and often go on to die of their disease respond poorly to anticonvulsant drug therapy, suggesting a need for new therapeutic targets. Previously, we reported that multiple GABAA receptor epilepsy mutations result in protein misfolding and abnormal receptor trafficking. We have now developed a model of a severe human genetic epileptic encephalopathy, the Gabrg2(+/Q390X) knock-in mouse. We found that, in addition to impairing inhibitory neurotransmission, mutant GABAA receptor γ2(Q390X) subunits accumulated and aggregated intracellularly, activated caspase 3 and caused widespread, age-dependent neurodegeneration. These findings suggest that the fundamental protein metabolism and cellular consequences of the epilepsy-associated mutant γ2(Q390X) ion channel subunit are not fundamentally different from those associated with neurodegeneration. Our results have far-reaching relevance for the identification of conserved pathological cascades and mechanism-based therapies that are shared between genetic epilepsies and neurodegenerative diseases.
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Jing-Qiong
authors.initials: JQ
authors.lastname: Kang
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Wangzhen
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Chengwen
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Computer Science and Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Xu
authors.affiliation: 1] Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [3] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Macdonald
mesh_terms: D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C546279:GABRG2 protein, human; C546280:Gabrg2 protein, mouse; D011963:Receptors, GABA-A