The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc

Greer, Paul L.; Hanayama, Rikinari; Bloodgood, Brenda L.; Mardinly, Alan R.; Lipton, David; Flavell, Steven W.; Kim, Tae Kyung; Griffith, Eric C.; Waldon, Zachary; Maehr, René; Ploegh, Hidde L.; Chowdhury, Shantanu; Worley, Paul F.; Steen, Judith A.; Greenberg, Michael E.

doi:10.1016/j.cell.2010.01.026

Cited by 564 publications

(600 citation statements)

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“…The ubiquitin ligase enzyme Ube3A is a member of the E3 ubiquitin ligase family. The disruption of its activity leads to Angelman syndrome, while in turn the Angelman syndrome was described in ASD with CNVs and mutations in UBE3A gene (Greer et al., 2010). In Ube3A knockout mice, electrophysiological studies demonstrated an impaired long‐term potentiation (LTP) in the hippocampus, which suggest that alteration of Ube3A results in the loss of neuronal plasticity.…”

Section: Reviewmentioning

confidence: 99%

“…In fact, Ube3A increases transcription through the myocyte enhancer factor 2 (MEF2) complex and regulates synapse function by ubiquitinating and degrading the synaptic protein Arc (activity‐regulated cytoskeleton‐associated protein). The role of Arc is to decrease long‐term potentiation by promoting the internalization of AMPA receptors, which are the mediators of the excitatory neurotransmission in the central nervous system (Greer et al., 2010). On another hand, a decrease in AMPAR expression at synapses has been observed in patients with fragile X syndrome.…”

Section: Reviewmentioning

confidence: 99%

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Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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“…Given that the ligase activity is important for the ubiquitination and degradation of target proteins, these observations suggest that disruption of UBE3A activity leads to inappropriately high levels of these target proteins and consequent neuronal dysfunction. While several candidate substrates have been discovered, AS-relevant targets leading to neural defects after UBE3A loss have yet to be identified [61,62]. In addition, because UBE3A lies within a region of chromosome 15 that is duplicated in a subset of heterogeneous ASDs, it remains possible that altered levels of UBE3A substrates might be a mechanism relevant to the etiology of autism [34,63].…”

Section: Cellular and Molecular Underpinnings Of Asmentioning

confidence: 99%

“…Recent studies using Drosophila melanogaster have identified potential fly Dube3a substrates [64]. In an attempt to take an unbiased approach to identify AS-relevant substrates of Ube3a, several laboratories have tried to compare the complement of ubiquitinated proteins in AS mouse brains with wild-type brains using quantitative mass spectrometry [52,62,65]. It is unclear from the results of these studies which substrates are affected directly or indirectly by Ube3a.…”

Section: Cellular and Molecular Underpinnings Of Asmentioning

confidence: 99%

Angelman Syndrome

et al. 2015

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In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2 % of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.Key Words Angelman syndrome . neurodevelopmental disorders . autism . ubiquitin ligase . Ube3a . Imprinting. Clinical OverviewIn 1965, the English physician Harry Angelman described 3 patients who presented with a stiff, jerky gait, absence of speech, excessive laughter, and seizures. The disorder that came to bear his name [Angelman syndrome (AS)] is now recognized to affect approximately 1 in 15,000 individuals and is characterized by motor dysfunction, severe intellectual disability, speech impairment, seizures, hyperactivity, and autism spectrum disorder (ASD) as a common comorbidity [1].Developmental delay in individuals with AS is usually observed within the first year of life. Though most individuals lack speech entirely, some who are mildly affected can acquire a few words. Receptive language is less impaired. Seizures occur in >80 % of patients, and onset is usually before the age of 3 years. Movement disorders include tremors, jerkiness, and ataxia. The characteristic behaviors of AS include mouthing of objects, happy demeanor with easily provoked laughter, attraction to water, hyperactivity, short attention span, and decreased sleeping (see recent reviews for more detailed description of the clinical phenotype [2][3][4]). These features of AS can be seen in other neurodevelopmental disorders, leading to a broad differential diagnosis [5], which has recently been reviewed (Table 1) [6]. Overlapping clinical features may indicate common neurophysiological pathways,

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“…One UBE3A target, activity-regulated cytoskeleton-associated protein, mediates surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) at excitatory synapses. In the absence of UBE3A expression, activity-regulated cytoskeleton-associated protein degradation is decreased, resulting in increased internalization of AMPARs and the development of impaired circuit function [25]. It has also been demonstrated that UBE3A plays a role in inhibitory synaptic function within the neocortex.…”

Section: Angelman Syndromementioning

confidence: 99%

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

et al. 2015

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Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental disorders characterized by language, social, cognitive, and behavioral abnormalities. ASD is a complex disorder with a heterogeneous etiology. The genetic architecture of autism is such that a variety of different rare mutations have been discovered, including rare monogenic conditions that involve autistic symptoms. Also, de novo copy number variants and single nucleotide variants contribute to disease susceptibility. Finally, autosomal recessive loci are contributing to our understanding of inherited factors. We will review the progress that the field has made in the discovery of these rare genetic variants in autism. We argue that mutation discovery of this sort offers an important opportunity to identify neurodevelopmental mechanisms in disease. The hope is that these mechanisms will show some degree of convergence that may be amenable to treatment intervention.

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The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc

Cited by 564 publications

References 45 publications

Autism throughout genetics: Perusal of the implication of ion channels

Autism throughout genetics: Perusal of the implication of ion channels

Angelman Syndrome

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

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