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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Aug 18, 2020 |
| Title |
Channelopathy pathogenesis in a human neural cell model of Angelman Syndrome |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Angelman syndrome (AS) is a neurogenetic developmental disorder that results from the loss of E3 ubiquitin ligase UBE3A due to mutations in or deletions of the maternally inherited UBE3A allele. While mouse models of AS have implicated abnormal synaptic signaling and plasticity underlying behavioral dysfunction, how the loss of UBE3A contributes to hyperactivity of neuronal networks seen in AS patients remains unclear. Here, by utilizing human induced neurons and 3D cortical organoids derived from AS patient iPSCs and CRISPR-Cas9 mediated UBE3A KO hESCs, we uncovered a novel role of UBE3A in suppressing neuronal hyperexcitability via ubiquitin-mediated degradation of BK channels. More importantly, augmented BK channel activity in neurons manifested as increased intrinsic excitability of neurons and network level bursting and synchronization, which can be pharmacologically normalized by BK antagonists. Our study has illustrated the utility of modeling neurological diseases with human neural cells, and our results have provided new insights into underlying pathophysiological mechanisms and potential therapeutic strategy in Angelman syndrome.
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| Overall design |
3 control vs 3 KO NGN2-induced neurons from H1 and H9 human embryonic stem cell lines
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| Contributor(s) |
Sun AX, Yuan Q, Fukuda M, Yu W, D'Agostino GA, Wang D, Tran H, Lokman H, Lim SW, Cook SA, Rackham OJ, Tan EK, Ng HH, Lim CT, Lim KL, Jiang Y, Je HS |
| Citation(s) |
31857479 |
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| Submission date |
Sep 20, 2018 |
| Last update date |
Aug 19, 2020 |
| Contact name |
Giuseppe Alessandro D'Agostino |
| E-mail(s) |
[email protected]
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| Organization name |
Lee Kong Chian School of Medicine - NTU
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| Lab |
Sarah Langley
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| Street address |
11 Mandalay Road
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| City |
Singapore |
| State/province |
Singapore |
| ZIP/Postal code |
308232 |
| Country |
Singapore |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA492237 |
| SRA |
SRP162220 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE120225_RNAseq_ensembl92_all.counts.txt.gz |
4.7 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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