The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc
Open accessAbstract
Angelman Syndrome is a debilitating neurological disorder caused by mutation of the E3 ubiquitin ligase Ube3A, a gene whose mutation has also recently been associated with autism spectrum disorders (ASDs). The function of Ube3A during nervous system development and how Ube3A mutations give rise to cognitive impairment in individuals with Angleman Syndrome and ASDs are not clear. We report here that experience-driven neuronal activity induces Ube3A transcription and that Ube3A then regulates excitatory synapse development by controlling the degradation of Arc, a synaptic protein that promotes the internalization of the AMPA subtype of glutamate receptors. We find that disruption of Ube3A function in neurons leads to an increase in Arc expression and a concomitant decrease in the number of AMPA receptors at excitatory synapses. We propose that this deregulation of AMPA receptor expression at synapses may contribute to the cognitive dysfunction that occurs in Angelman Syndrome and possibly other ASDs.
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Array tomography is a powerful tool for high resolution imaging and quantification of synaptic density in vivo.
“using array tomography (AT), a powerful tool for high resolution imaging and quantification of synaptic density in vivo (Greer et al., 2010; Margolis et al., 2010; Micheva and Smith, 2007; Ross et al., 2010).”
From Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner (2012) · cites this paper as Greer et al., 2010
The Results section describes array tomography as imaging ultrathin brain sections to visualize synapses in 3-D, and reports synaptic-puncta densities in mouse hippocampi. Experimental Procedures (Array Tomography) specifies 100 nm sections and synapse counting. The imaging was performed on fixed, excised tissue, however, not in vivo. (LLM, conf=0.84)
Experimental — accuracy not yet measuredUbe3A expression is up-regulated by neuronal activity.
“Ube3A expression is up-regulated by neuronal activity”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [89]
One of the best-studied targets of UBE3A is the neuronal activity-regulated protein Arc.
“one of the best-studied targets of UBE3A is the neuronal activity-regulated protein Arc89”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [89]
Neurons from mice with maternal Ube3A deletion express increased levels of Arc protein.
“neurons from these mice express increased levels of Arc protein.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [89]
Loss of experience-dependent induction of UBE3A mRNA during postnatal development may contribute to Angelman syndrome, and increased activity-dependent UBE3A expression may underlie some forms of ASD.
“it has therefore been suggested that a loss of experience-dependent induction of the UBE3A mRNA during post-natal development may contribute to Angelman syndrome, and increased activity-dependent UBE3A expression may underlie some forms of ASD89.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [89]
UBE3A, FMRP, and TSC mutations may converge in ASD aetiology.
“suggesting a possible convergence point for UBE3A, FMRP and TSC mutations in the aetiology of ASD.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [89]
UBE3A mediates ubiquitination and degradation of Arc.
“UBE3A was found to mediate the ubiquitination and degradation of Arc89.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [89]
Dysregulation of Arc levels and AMPA receptor expression at synapses may contribute to ASD phenotypes in Angelman syndrome and possibly ASD involving CNVs on chromosome 15.
“Thus, the dysregulation of Arc levels and AMPA receptor expression at synapses may contribute to the ASD phenotypes observed in Angelman syndrome and possibly ASD that involve CNVs on chromosome 15.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [89]
Reference 89 gives insight into the molecular mechanisms of Angelman syndrome and the role of neuronal activity in regulating Ube3A and its targets.
“This study provides insight into the molecular mechanisms underlying Angelman syndrome and the role of neuronal activity in regulating Ube3A and its targets.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [89]
Increased Arc expression in the absence of UBE3A results in decreased AMPA receptor cell surface expression and decreased AMPA receptor-mediated currents.
“The increased level of Arc expression in the absence of UBE3A results in decreased AMPA receptor cell surface expression and a decrease in the AMPA receptor-mediated currents89.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [89]
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References 43 · Cited by 30
- Authors
- Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., Kim, T.-K., Griffith, E. C., Waldon, Z., Maehr, R., Ploegh, H. L., Chowdhury, S., Worley, P. F., Steen, J., & Greenberg, M. E.
- Affiliations
- Harvard University (US)
- Boston Children's Hospital (US)
- Whitehead Institute for Biomedical Research (US)
- Johns Hopkins University (US)
- Corresponding author
- Greenberg, Michael E.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-03
- Volume
- 140
- Issue
- 5
- Pages
- 704-716
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2843143
- OpenAlex
- W1581958701
- Cited by
- 30
- References
- 43
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 1 · 2021: 5 · 2020: 1 · 2019: 5 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 2
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH 53608, R01MH053608)
- National Institute of Neurological Disorders and Stroke (R01NS028829, R37NS028829, NS 28829)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- Angelman syndrome, UBE3A, Arc, ubiquitination, AMPA receptor internalization, autism spectrum disorder, cognitive impairment, E3 ubiquitin ligase
- MeSH terms
- Animals, Cells, Cultured, Cognition, Cytoskeletal Proteins, Humans, Nerve Tissue Proteins, Synapses, Angelman Syndrome, Receptors, AMPA, Mice, Knockout, Ubiquitin-Protein Ligases, Mice, Ubiquitination
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