The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration.
The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration.
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DOI：
10.1038/nn.4024
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发表时间：
2015-07
影响因子：
25
通讯作者：
Macdonald, Robert L.
中科院分区：
文献类型：
--
作者：
Kang, Jing-Qiong;Shen, Wangzhen;Zhou, Chengwen;Xu, Dong;Macdonald, Robert L.
遗传性癫痫和神经退行性疾病是两种常见的神经系统疾病，传统上被认为是无关的。部分严重遗传性癫痫患者的发育受损并经常死亡，对抗惊厥药物治疗的反应很差，这表明需要新的治疗靶点。在此之前，我们报道了多个GABAA受体癫痫突变导致蛋白质错误折叠和异常受体转运。在这里，我们建立了一个新的人类遗传性癫痫脑病模型--Gabrg2+/Q390X敲入小鼠，除了损害抑制性神经传递外，突变的GaBAA受体γ2(Q390X)亚单位在细胞内聚集和聚集，激活caspase3，导致广泛的、年龄相关的神经变性。这些新的发现表明，癫痫相关突变γ2(Q390X)离子通道亚单位的基本蛋白质代谢和细胞后果与与神经退行性变相关的那些没有根本不同。这项研究对于识别遗传性癫痫和神经退行性疾病重叠的保守病理级联和基于机制的治疗具有深远的意义。
Genetic epilepsy and neurodegenerative diseases are two common neurological disorders conventionally viewed as being unrelated. A subset of patients with severe genetic epilepsies with impaired development and often death respond poorly to anticonvulsant drug therapy, suggesting a need for new therapeutic targets. Previously, we reported that multiple GABAA receptor epilepsy mutations caused protein misfolding and abnormal receptor trafficking. Here we establish in a novel model of a severe human genetic epileptic encephalopathy, the Gabrg2+/Q390X knock-in mouse, 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 novel 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. The study has far-reaching significance for identification of conserved pathological cascades and mechanism-based therapies that overlap genetic epilepsies and neurodegenerative diseases.
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