新加坡国立大学Hyunsoo Shawn Je、新加坡国立神经研究所Alfred Xuyang Sun等研究人员，合作发现人类Angelman综合征（AS）神经元模型中的钾通道功能异常。这一研究成果发表在2019年12月20日出版的国际学术期刊《科学》上。
使用人类神经元和大脑类器官体，研究人员证明，泛素蛋白连接酶E3A（UBE3A）通过泛素介导的钙依赖性和电压依赖性大型钾离子（BK）通道降解来抑制神经元过度兴奋。
研究人员提供的证据表明，增加的BK通道活动表现为单个神经元的内在兴奋性增加以及随后的神经网络同步。BK拮抗剂使人和小鼠神经元的神经元兴奋性正常化，并改善了AS小鼠模型的癫痫发作敏感性。这些发现表明，BK通道病是AS癫痫的基础，并证明能够使用人类细胞来模拟人类发育疾病。
据悉，UBE3A基因的破坏会导致AS。虽然AS模型小鼠具有相关的突触功能障碍和可塑性随异常行为而改变，但尚不清楚相似或其他机制是否会导致AS患者出现神经网络过度活跃和癫痫易感性。
附：英文原文
Title: Potassium channel dysfunction in human neuronal models of Angelman syndrome
Author: Alfred Xuyang Sun, Qiang Yuan, Masahiro Fukuda, Weonjin Yu, Haidun Yan, Grace Gui Yin Lim, Mui Hoon Nai, Giuseppe Alessandro D’Agostino, Hoang-Dai Tran, Yoko Itahana, Danlei Wang, Hidayat Lokman, Koji Itahana, Stephanie Wai Lin Lim, Jiong Tang, Ya Yin Chang, Menglan Zhang, Stuart A. Cook, Owen J. L. Rackham, Chwee Teck Lim, Eng King Tan, Huck Hui Ng, Kah Leong Lim, Yong-Hui Jiang, Hyunsoo Shawn Je
Issue&Volume: 2019/12/20
Abstract: 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.
DOI: 10.1126/science.aav5386
Source:
https://science.sciencemag.org/content/366/6472/1486