Potassium channel dysfunction in human neuronal models of Angelman syndrome.
Potassium channel dysfunction in human neuronal models of Angelman syndrome.
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DOI：
10.1126/science.aav5386
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发表时间：
2019-12-20
期刊：
影响因子：
--
通讯作者：
Je HS
中科院分区：
文献类型：
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作者：
Sun AX;Yuan Q;Fukuda M;Yu W;Yan H;Lim GGY;Nai MH;D'Agostino GA;Tran HD;Itahana Y;Wang D;Lokman H;Itahana K;Lim SWL;Tang J;Chang YY;Zhang M;Cook SA;Rackham OJL;Lim CT;Tan EK;Ng HH;Lim KL;Jiang YH;Je HS
泛素蛋白连接酶 E3A (UBE3A) 基因的破坏会导致天使综合征 (AS)。尽管 AS 模型小鼠的突触功能障碍和可塑性改变与异常行为相关，但类似或其他机制是否导致 AS 患者的网络过度活跃和癫痫易感性仍不清楚。使用人类神经元和大脑类器官，我们证明 UBE3A 通过泛素介导的钙和电压依赖性大钾 (BK) 通道的降解来抑制神经元过度兴奋。我们提供的证据表明，增强的 BK 通道活性表现为单个神经元内在兴奋性的增加以及随后的网络同步。 BK 拮抗剂使人和小鼠神经元的神经元兴奋性正常化，并改善 AS 小鼠模型的癫痫易感性。我们的研究结果表明 BK 通道病是 AS 癫痫的基础，并支持使用人类细胞来模拟人类发育疾病。
Disruptions in the ubiquitin protein ligase E3A (UBE3A) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases.