Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model
Open accessAbstract
Angelman syndrome (AS) is a severe neurodevelopmental disorder that results from loss of function of the maternal ubiquitin protein ligase E3A (UBE3A) allele. Due to neuron-specific imprinting, the paternal UBE3A copy is silenced. Previous studies in murine models have demonstrated that strategies to activate the paternal Ube3a allele are feasible; however, a recent study showed that pharmacological Ube3a gene reactivation in adulthood failed to rescue the majority of neurocognitive phenotypes in a murine AS model. Here, we performed a systematic study to investigate the possibility that neurocognitive rescue can be achieved by reinstating Ube3a during earlier neurodevelopmental windows. We developed an AS model that allows for temporally controlled Cre-dependent induction of the maternal Ube3a allele and determined that there are distinct neurodevelopmental windows during which Ube3a restoration can rescue AS-relevant phenotypes. Motor deficits were rescued by Ube3a reinstatement in adolescent mice, whereas anxiety, repetitive behavior, and epilepsy were only rescued when Ube3a was reinstated during early development. In contrast, hippocampal synaptic plasticity could be restored at any age. Together, these findings suggest that Ube3a reinstatement early in development may be necessary to prevent or rescue most AS-associated phenotypes and should be considered in future clinical trial design.
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Reinstating Ube3a in Ube3a-knockout mice restores synaptic plasticity at any age, but behaviour improves only when reinstatement occurs during early development.
“reinstatement of ubiquitin protein ligase E3A (Ube3a) in Ube3a-KO mice can restore synaptic plasticity at any age, but behaviour can only improve when reinstatement occurs during early development78.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [78]
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- E-mail: y.elgersma@ erasmusmc.nl. (mouse α-E6AP [E8655 Sigma-Aldrich, 1:2,000] in 2% NHS, 0.5% Triton X-100). The next day the slices were incubated with the sec- ondary antibody (α-mouse HRP; Dako; 1:200), which was detected by DAB as the chromogen. Statistics. All data were statistically analyzed using IBM SPSS soft- ware, and P values less than 0.05 were considered significant. Statisti- cal analysis was performed using 1-way ANOVA or 2-way ANOVA with Bonferroni's post hoc comparison. Study approval. All animal experiments were approved by the Dutch Animal Experiment Committee (Dierexperimenten commissie
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- Authors
- Silva-Santos, S., van Woerden, G. M., Bruinsma, C. F., Mientjes, E., Jolfaei, M. A., Distel, B., Kushner, S. A., & Elgersma, Y.
- Affiliations
- Universidade do Porto (PT)
- Erasmus MC (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- Venue
- Journal of Clinical Investigation
- Published
- 2015-04-13
- Volume
- 125
- Issue
- 5
- Pages
- 2069-2076
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4463212
- OpenAlex
- W2041807010
- Cited by
- 238
- References
- 26
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 29 · 2023: 26 · 2022: 26 · 2021: 23 · 2020: 33 · 2019: 17 · 2018: 16 · 2017: 16 · 2016: 11 · 2015: 9
- FWCI
- 11.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Simons Foundation (275234)
- Angelman Syndrome Foundation
- Simons Foundation Autism Research Initiative
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- Angelman syndrome, UBE3A, genomic imprinting, motor impairment, anxiety, repetitive behavior, epilepsy, hippocampal synaptic plasticity, mouse model
- MeSH terms
- Age Factors, Animals, Anxiety, Cerebellum, Cerebral Cortex, Disease Models, Animal, Epilepsy, Female, Genes, Synthetic, Hippocampus, Male, Movement Disorders, Neuronal Plasticity, Phenotype, Recombinant Fusion Proteins, Stereotyped Behavior, Tamoxifen, Angelman Syndrome, Genomic Imprinting, Gene Expression Regulation, Developmental, Ubiquitin-Protein Ligases, Mice
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