Imperial College London
Alternate

ProfessorStuartCook

Faculty of Medicine, Institute of Clinical Sciences

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 3313 1346stuart.cook

 
 
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Location

 

RF 16Sydney StreetRoyal Brompton Campus

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Summary

 

Publications

Citation

BibTex format

@article{Sun:2019:10.1126/science.aav5386,
author = {Sun, AX and Yuan, Q and Fukuda, M and Yu, W and Yan, H and Lim, GGY and Nai, MH and D'Agostino, GA and Tran, H-D and Itahana, Y and Wang, D and Lokman, H and Itahana, K and Lim, SWL and Tang, J and Chang, YY and Zhang, M and Cook, SA and Rackham, OJL and Lim, CT and Tan, EK and Ng, HH and Lim, KL and Jiang, Y-H and Je, HS},
doi = {10.1126/science.aav5386},
journal = {Science},
pages = {1486--1492},
title = {Potassium channel dysfunction in human neuronal models of Angelman syndrome},
url = {http://dx.doi.org/10.1126/science.aav5386},
volume = {366},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Sun,AX
AU  - Yuan,Q
AU  - Fukuda,M
AU  - Yu,W
AU  - Yan,H
AU  - Lim,GGY
AU  - Nai,MH
AU  - D'Agostino,GA
AU  - Tran,H-D
AU  - Itahana,Y
AU  - Wang,D
AU  - Lokman,H
AU  - Itahana,K
AU  - Lim,SWL
AU  - Tang,J
AU  - Chang,YY
AU  - Zhang,M
AU  - Cook,SA
AU  - Rackham,OJL
AU  - Lim,CT
AU  - Tan,EK
AU  - Ng,HH
AU  - Lim,KL
AU  - Jiang,Y-H
AU  - Je,HS
DO  - 10.1126/science.aav5386
EP  - 1492
PY  - 2019///
SN  - 0036-8075
SP  - 1486
TI  - Potassium channel dysfunction in human neuronal models of Angelman syndrome
T2  - Science
UR  - http://dx.doi.org/10.1126/science.aav5386
UR  - https://www.ncbi.nlm.nih.gov/pubmed/31857479
UR  - http://hdl.handle.net/10044/1/105577
VL  - 366
ER  -
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