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: Jing-Qiong Kang, Wangzhen Shen, Chengwen Zhou, Dong Xu, Robert L Macdonald
• Journal: Nature neuroscience (Nat Neurosci) Vol. 18 Issue 7 Pg. 988-96 (Jul 2015) ISSN: 1546-1726 [Electronic] United States
• PMID: 26005849 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• GABRG2 protein, human
• Gabrg2 protein, mouse
• Receptors, GABA-A

Topics

• Adult
• Animals
• Disease Models, Animal
• Epilepsy (genetics, metabolism, pathology, physiopathology)
• Female
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mutation
• Neurodegenerative Diseases (genetics, metabolism, pathology, physiopathology)
• Receptors, GABA-A (genetics, metabolism)
• Young Adult