The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration

摘要: Genetic epilepsy and neurodegenerative diseases are two common neurological disorders that conventionally viewed as being unrelated. A subset of patients with severe genetic epilepsies who have impaired development often go on to die their disease respond poorly anticonvulsant drug therapy, suggesting a need for new therapeutic targets. Previously, we reported multiple GABAA receptor mutations result in protein misfolding abnormal trafficking. We now developed model human epileptic encephalopathy, the Gabrg2(+/Q390X) knock-in mouse. found that, addition impairing inhibitory neurotransmission, mutant γ2(Q390X) subunits accumulated aggregated intracellularly, activated caspase 3 caused widespread, age-dependent neurodegeneration. These findings suggest fundamental metabolism cellular consequences epilepsy-associated ion channel subunit not fundamentally different from those associated Our results far-reaching relevance identification conserved pathological cascades mechanism-based therapies shared between diseases.