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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.
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]
Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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DbLabel: Psychology and Behavioral Sciences Collection
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PubTypeId: academicJournal
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  Data: Potassium channel dysfunction in human neuronal models of Angelman syndrome.
– Name: Author
  Label: Authors
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  Data: <searchLink fieldCode="AR" term="%22Alfred+Xuyang+Sun%22">Alfred Xuyang Sun</searchLink><br /><searchLink fieldCode="AR" term="%22Qiang+Yuan%22">Qiang Yuan</searchLink><br /><searchLink fieldCode="AR" term="%22Masahiro+Fukuda%22">Masahiro Fukuda</searchLink><br /><searchLink fieldCode="AR" term="%22Weonjin+Yu%22">Weonjin Yu</searchLink><br /><searchLink fieldCode="AR" term="%22Haidun+Yan%22">Haidun Yan</searchLink><br /><searchLink fieldCode="AR" term="%22Grace+Gui+Yin+Lim%22">Grace Gui Yin Lim</searchLink><br /><searchLink fieldCode="AR" term="%22Mui+Hoon+Nai%22">Mui Hoon Nai</searchLink><br /><searchLink fieldCode="AR" term="%22D’Agostino%2C+Giuseppe+Alessandro%22">D’Agostino, Giuseppe Alessandro</searchLink><br /><searchLink fieldCode="AR" term="%22Hoang-Dai+Tran%22">Hoang-Dai Tran</searchLink><br /><searchLink fieldCode="AR" term="%22Yoko+Itahana%22">Yoko Itahana</searchLink><br /><searchLink fieldCode="AR" term="%22Danlei+Wang%22">Danlei Wang</searchLink><br /><searchLink fieldCode="AR" term="%22Lokman%2C+Hidayat%22">Lokman, Hidayat</searchLink><br /><searchLink fieldCode="AR" term="%22Itahana%2C+Koji%22">Itahana, Koji</searchLink><br /><searchLink fieldCode="AR" term="%22Wai+Lin+Lim%2C+Stephanie%22">Wai Lin Lim, Stephanie</searchLink><br /><searchLink fieldCode="AR" term="%22Jiong+Tang%22">Jiong Tang</searchLink><br /><searchLink fieldCode="AR" term="%22Ya+Yin+Chang%22">Ya Yin Chang</searchLink><br /><searchLink fieldCode="AR" term="%22Menglan+Zhang%22">Menglan Zhang</searchLink><br /><searchLink fieldCode="AR" term="%22Cook%2C+Stuart+A%2E%22">Cook, Stuart A.</searchLink><br /><searchLink fieldCode="AR" term="%22Rackham%2C+Owen+J%2E+L%2E%22">Rackham, Owen J. L.</searchLink><br /><searchLink fieldCode="AR" term="%22Chwee+Teck+Lim%22">Chwee Teck Lim</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Science+%28pre-March+2025%29%22">Science (pre-March 2025)</searchLink>. 12/20/2019, Vol. 366 Issue 6472, p1486-1492. 7p. 4 Diagrams.
– Name: Subject
  Label: Subjects
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Ubiquitin+ligases%22">Ubiquitin ligases</searchLink><br /><searchLink fieldCode="DE" term="%22Neurons%22">Neurons</searchLink><br /><searchLink fieldCode="DE" term="%22Potassium+channels%22">Potassium channels</searchLink><br /><searchLink fieldCode="DE" term="%22Angelman+syndrome%22">Angelman syndrome</searchLink><br /><searchLink fieldCode="DE" term="%22Laboratory+mice%22">Laboratory mice</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=140501631
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      – Type: doi
        Value: 10.1126/science.aav5386
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      – Code: eng
        Text: English
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        PageCount: 7
        StartPage: 1486
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      – SubjectFull: Ubiquitin ligases
        Type: general
      – SubjectFull: Neurons
        Type: general
      – SubjectFull: Potassium channels
        Type: general
      – SubjectFull: Angelman syndrome
        Type: general
      – SubjectFull: Laboratory mice
        Type: general
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      – TitleFull: Potassium channel dysfunction in human neuronal models of Angelman syndrome.
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              Text: 12/20/2019
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