UBE3A: An E3 Ubiquitin Ligase With Genome-Wide Impact in Neurodevelopmental Disease

Lopez, S. Jesse; Segal, David J.; LaSalle, Janine M.

doi:10.3389/fnmol.2018.00476

Cited by 54 publications

(39 citation statements)

References 69 publications

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“…The molecular mechanisms behind the sociability disruption in 15q11-13-related syndromes have been widely studied and chiefly associated with UBE3A [134,135], thought to be the main responsible for the increased risk of ASD in PWS patients [136,137]. Transgenic mice carrying an Ube3a duplication showed a dose-dependency of its gene product to sociability manifestations, in particular fact, mice with maternally-inherited Ube3a deletion displayed a prolonged preference interaction with social stimuli in the threechamber social approach task [134].…”

Section: Q11-q13mentioning

confidence: 99%

The sociability spectrum: evidence from reciprocal genetic copy number variations

2020

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Sociability entails some of the most complex behaviors processed by the central nervous system. It includes the detection, integration, and interpretation of social cues and elaboration of context-specific responses that are quintessentially species-specific. There is an ever-growing accumulation of molecular associations to autism spectrum disorders (ASD), from causative genes to endophenotypes across multiple functional layers; these however, have rarely been put in context with the opposite manifestation featured in hypersociability syndromes. Genetic copy number variations (CNVs) allow to investigate the relationships between gene dosage and its corresponding phenotypes. In particular, CNVs of the 7q11.23 locus, which manifest diametrically opposite social behaviors, offer a privileged window to look into the molecular substrates underlying the developmental trajectories of the social brain. As by definition sociability is studied in humans postnatally, the developmental fluctuations causing social impairments have thus far remained a black box. Here, we review key evidence of molecular players involved at both ends of the sociability spectrum, focusing on genetic and functional associations of neuroendocrine regulators and synaptic transmission pathways. We then proceed to propose the existence of a molecular axis centered around the paradigmatic dosage imbalances at the 7q11.23 locus, regulating networks responsible for the development of social behavior in humans and highlight the key role that neurodevelopmental models from reprogrammed pluripotent cells will play for its understanding.

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Section: Q11-q13mentioning

confidence: 99%

The sociability spectrum: evidence from reciprocal genetic copy number variations

2020

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“…Other reviews [56] highlight the mechanistic function of UBE3A, describing its association with several proteasome receptors, like DDI1 [57,58] or PSMD4 but also with proteasome itself, which is thought to control the proteolysis [59]. AS-associated point mutations in UBE3A N-terminus show impaired PSMD4 binding [60].…”

Section: Molecular Biology Of Ube3a a Proteasome Regulator And Modulmentioning

confidence: 99%

Molecular Evolution, Neurodevelopmental Roles and Clinical Significance of HECT-Type UBE3 E3 Ubiquitin Ligases

Ambrozkiewicz

Cuthill

Harnett

et al. 2020

Cells

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Protein ubiquitination belongs to the best characterized pathways of protein degradation in the cell; however, our current knowledge on its physiological consequences is just the tip of an iceberg. The divergence of enzymatic executors of ubiquitination led to some 600–700 E3 ubiquitin ligases embedded in the human genome. Notably, mutations in around 13% of these genes are causative of severe neurological diseases. Despite this, molecular and cellular context of ubiquitination remains poorly characterized, especially in the developing brain. In this review article, we summarize recent findings on brain-expressed HECT-type E3 UBE3 ligases and their murine orthologues, comprising Angelman syndrome UBE3A, Kaufman oculocerebrofacial syndrome UBE3B and autism spectrum disorder-associated UBE3C. We summarize evolutionary emergence of three UBE3 genes, the biochemistry of UBE3 enzymes, their biology and clinical relevance in brain disorders. Particularly, we highlight that uninterrupted action of UBE3 ligases is a sine qua non for cortical circuit assembly and higher cognitive functions of the neocortex.

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“…It might exist other unknown factors regulating the activity and expression of Ube3a. In the nucleus, Ube3a binds to specific promoter region(s) and acts as a transcriptional coactivator (Lopez et al, ; Vatsa & Jana, ) [Color figure can be viewed at wileyonlinelibrary.com]…”

Section: Conclusion and Perspectivementioning

confidence: 99%

“…The success of the ketogenic diet, extra‐synaptic GABAA receptor agonist THIP, and the recent exciting results of the clinical trial with gaboxadol (OV101; Phase1 NCT03109756 and Phase2 NCT02996305) seem promising for the development of more symptoms‐targeted drugs. Besides, the uncovered role of Ube3a as a transcription coactivator opens another window for AS treatments (Lopez, Segal, & LaSalle, ; Vatsa & Jana, ). Moreover, the Ube3a cell type and isoform‐specific studies will further refresh our understanding of AS.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Towards an understanding of Angelman syndrome in mice studies

Yang

2019

J of Neuroscience Research

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Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe mental retardation, absence of speech, abnormal motor coordination, abnormal EEG, and spontaneous seizure. AS is caused by a deficiency in the ubiquitin ligase E3A (Ube3a) gene product, known to play a dual role as both ubiquitin ligase and transcription coactivator. In AS animal models, multiple Ube3a substrates are accumulated in neurons. So far, studies in mouse models have either aimed at re‐expressing Ube3a or manipulating downstream signaling pathways. Reintroducing Ube3a in AS mice showed promising results but may have two caveats. First, it may cause an overdosage in the Ube3a expression, which in turn is known to contribute to autism spectrum disorders. Second, in mutation cases, the exogenous Ube3a may have to compete with the mutated endogenous form. Such two caveats left spaces for developing therapies or interventions directed to targets downstream Ube3a. Notably, Ube3a expression is dynamically regulated by neuronal activity and plays a crucial role in synaptic plasticity. The abnormal synaptic plasticity uncovered in AS mice has been frequently rescued, but circuits symptoms like seizure are resistant to treatment. Future investigations are needed to further clarify the function (s) of Ube3a during development. Here I reviewed the recently identified major Ube3a substrates and signaling pathways involved in AS pathology, the Ube3a expression, imprinting and evolution, the AS mouse models that have been generated and inspired therapeutic potentials, and finally proposed some future explorations to better understand the AS pathology.

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UBE3A: An E3 Ubiquitin Ligase With Genome-Wide Impact in Neurodevelopmental Disease

Cited by 54 publications

References 69 publications

The sociability spectrum: evidence from reciprocal genetic copy number variations

The sociability spectrum: evidence from reciprocal genetic copy number variations

Molecular Evolution, Neurodevelopmental Roles and Clinical Significance of HECT-Type UBE3 E3 Ubiquitin Ligases

Towards an understanding of Angelman syndrome in mice studies

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