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Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells
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Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells
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Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells
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Journal Article
Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells
2017
Overview
Angelman syndrome (AS) is a neurogenetic disorder caused by deletion of the maternally inherited
UBE3A
allele and is characterized by developmental delay, intellectual disability, ataxia, seizures and a happy affect. Here, we explored the underlying pathophysiology using induced pluripotent stem cell-derived neurons from AS patients and unaffected controls. AS-derived neurons showed impaired maturation of resting membrane potential and action potential firing, decreased synaptic activity and reduced synaptic plasticity. These patient-specific differences were mimicked by knocking out
UBE3A
using CRISPR/Cas9 or by knocking down
UBE3A
using antisense oligonucleotides. Importantly, these phenotypes could be rescued by pharmacologically unsilencing paternal
UBE3A
expression. Moreover, selective effects of
UBE3A
disruption at late stages of
in vitro
development suggest that changes in action potential firing and synaptic activity may be secondary to altered resting membrane potential. Our findings provide a cellular phenotype for investigating pathogenic mechanisms underlying AS and identifying novel therapeutic strategies.
Angelman syndrome (AS) is characterized by developmental delay and intellectual disability, but the underlying pathophysiology is not well understood. Here the authors use induced pluripotent stem cell-derived neurons from AS patients and find impaired maturation of resting membrane potential and action potential firing, and defects in synaptic activity associated with the disease.
