Potassium channel dysfunction in human neuronal models of Angelman syndrome.
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| Title: | Potassium channel dysfunction in human neuronal models of Angelman syndrome. |
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| Authors: | Alfred Xuyang Sun, Qiang Yuan, Masahiro Fukuda, Weonjin Yu, Haidun Yan, Grace Gui Yin Lim, Mui Hoon Nai, D’Agostino, Giuseppe Alessandro, Hoang-Dai Tran, Yoko Itahana, Danlei Wang, Lokman, Hidayat, Itahana, Koji, Wai Lin Lim, Stephanie, Jiong Tang, Ya Yin Chang, Menglan Zhang, Cook, Stuart A., Rackham, Owen J. L., Chwee Teck Lim |
| Source: | Science (pre-March 2025). 12/20/2019, Vol. 366 Issue 6472, p1486-1492. 7p. 4 Diagrams. |
| Subjects: | Ubiquitin ligases, Neurons, Potassium channels, Angelman syndrome, Laboratory mice |
| 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 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. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| 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 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. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.aav5386 |
