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DOI | 10.1126/science.aav5386 |
Potassium channel dysfunction in human neuronal models of Angelman syndrome | |
Sun, Alfred Xuyang1; 39;Agostino, Giuseppe Alessandro2 | |
2019-12-20 | |
发表期刊 | SCIENCE |
ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2019 |
卷号 | 366期号:6472页码:1486-+ |
文章类型 | Article |
语种 | 英语 |
国家 | Singapore; USA |
英文摘要 | 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 calciumand 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. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000503861000049 |
WOS关键词 | PLURIPOTENT STEM-CELLS ; UBIQUITIN LIGASE ; UBE3A ; BK ; INDUCTION ; NETWORKS ; INSIGHTS ; MUTATION ; SEIZURE ; CORTEX |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/226503 |
专题 | 环境与发展全球科技态势 |
作者单位 | 1.Natl Neurosci Inst, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore; 2.Genome Inst Singapore, 60 Biopolis St, Singapore 138672, Singapore; 3.Natl Univ Singapore, Grad Sch Integrat Sci & Engn, 28 Med Dr, Singapore 117456, Singapore; 4.Duke NUS Med Sch, Signature Program Neurosci & Behav Disorders, 8 Coll Rd, Singapore 169857, Singapore; 5.Duke Univ, Sch Med, Dept Neurobiol, Durham, NC 27710 USA; 6.Natl Univ Singapore, Dept Biomed Engn, Singapore 117576, Singapore; 7.Duke NUS Med Sch, Program Cardiovasc & Metab Disorders, 8 Coll Rd, Singapore 169857, Singapore; 8.Duke NUS Med Sch, Program Canc & Stem Cell Biol, 8 Coll Rd, Singapore 169857, Singapore; 9.ASTAR, Singapore Bioimaging Consortium, Singapore 138667, Singapore; 10.Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore; 11.Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore; 12.Univ Utah, Dept Neurobiol & Anat, Salt Lake City, UT 84112 USA; 13.Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA |
推荐引用方式 GB/T 7714 | Sun, Alfred Xuyang,39;Agostino, Giuseppe Alessandro. Potassium channel dysfunction in human neuronal models of Angelman syndrome[J]. SCIENCE,2019,366(6472):1486-+. |
APA | Sun, Alfred Xuyang,&39;Agostino, Giuseppe Alessandro.(2019).Potassium channel dysfunction in human neuronal models of Angelman syndrome.SCIENCE,366(6472),1486-+. |
MLA | Sun, Alfred Xuyang,et al."Potassium channel dysfunction in human neuronal models of Angelman syndrome".SCIENCE 366.6472(2019):1486-+. |
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