E6AP in the Brain: One Protein, Dual Function, Multiple Diseases

Hokayem, Jimmy El; Nawaz, Zafar

doi:10.1007/s12035-013-8563-y

Cited by 24 publications

(29 citation statements)

References 115 publications

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“…Ubiquitination involves a three-step process: 1) activation of ubiquitin by an E1 enzyme, 2) transfer to an E2 conjugating enzyme, and 3) covalent ligation of ubiquitin to the protein substrate by an E3 ligase; E6-AP is one of many E3 ligases. E6-AP also interacts with proteins involved in such cellular functions as cell-cycle regulation and synaptic function and plasticity,99,100 and acts as a transcriptional co-activator of steroid hormone receptors 101,102. The C-terminus of E6-AP is a functionally important and highly conserved domain that is shared by a family of proteins (HECT domain), of which E6-AP is the founding member.…”

Section: Molecular Pathogenesismentioning

confidence: 99%

Angelman syndrome: review of clinical and molecular aspects

Bird

2014

TACG

182

155

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“Angelman syndrome” (AS) is a neurodevelopmental disorder whose main features are intellectual disability, lack of speech, seizures, and a characteristic behavioral profile. The behavioral features of AS include a happy demeanor, easily provoked laughter, short attention span, hypermotoric behavior, mouthing of objects, sleep disturbance, and an affinity for water. Microcephaly and subtle dysmorphic features, as well as ataxia and other movement disturbances, are additional features seen in most affected individuals. AS is due to deficient expression of the ubiquitin protein ligase E3A (UBE3A) gene, which displays paternal imprinting. There are four molecular classes of AS, and some genotype–phenotype correlations have emerged. Much remains to be understood regarding how insufficiency of E6-AP, the protein product of UBE3A, results in the observed neurodevelopmental deficits. Studies of mouse models of AS have implicated UBE3A in experience-dependent synaptic remodeling.

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Section: Molecular Pathogenesismentioning

confidence: 99%

Angelman syndrome: review of clinical and molecular aspects

Bird

2014

TACG

182

155

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“…These effects were decreased, both neurotransmitter synthesis and activity, in Dube3a loss of function animals [16]. How transcriptional regulation involving UBE3A relates to the pathogenesis of UBE3A-related disorders remains unclear [17], but whole genome expression studies on both Angelman syndrome and 15q Duplication syndrome derived cell lines [18] may shed some light on the transcriptional regulatory roles of UBE3A in neurons and other tissues.…”

Section: Ube3a Function and Expressionmentioning

confidence: 99%

Epigenetic Regulation of UBE3A and Roles in Human Neurodevelopmental Disorders

2015

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Summary The E3 ubiquitin ligase protein UBE3A, also known as E6-AP, has a multitude of ascribed functions and targets relevant to human health and disease. Epigenetic regulation of the UBE3A gene by parentally imprinted noncoding transcription within human chromosome 15q11.2-q13.3 is responsible for the maternal-specific effects of 15q11.2-q13.3 deletion or duplication disorders. Here, we review the evidence for diverse and emerging roles for UBE3A in the proteasome, synapse, and nucleus in regulating protein stability and transcription as well as the current mechanistic understanding of UBE3A imprinting in neurons. Angelman and Dup15q syndromes as well as experimental models of these neurodevelopmental disorders are highlighted as improving understanding of UBE3A and its complex regulation for improving therapeutic strategies.

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“…Mutations in this protein are associated with deficits in contextual learning (fear conditioning) and with decreased LTP (53). Interestingly, this ligase is associated with the neurological disorder known as Angelman syndrome (54). E6-AP ligase mediates the polyubiquitination of Arc, and its disruption increases Arc expression and thereby decreases the number of AMPA receptors at synapses (55).…”

Section: Local Protein Degradationmentioning

confidence: 99%

The Regulation of Synaptic Protein Turnover

Álvarez-Castelao

2015

Journal of Biological Chemistry

100

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Emerging evidence indicates that protein synthesis and degradation are necessary for the remodeling of synapses. These two processes govern cellular protein turnover, are tightly regulated, and are modulated by neuronal activity in time and space. The anisotropic anatomy of the neurons presents a challenge for the study of protein turnover, but the understanding of protein turnover in neurons and its modulation in response to activity can help us to unravel the fine-tuned changes that occur at synapses in response to activity. Here we review the key experimental evidence demonstrating the role of protein synthesis and degradation in synaptic plasticity, as well as the turnover rates of specific neuronal proteins.The human brain is composed of a trillion neurons with complex and intricate arbors, which are interconnected by synapses (1). Synapses are highly dynamic in number and shape as a consequence of the continuous remodeling of neural circuits. A change in synaptic transmission elicited by neural activity is collectively called "synaptic plasticity," and learning and memory rely, at least in part, on this process. Synapses are made up of proteins, including receptors for neurotransmitters, scaffolding molecules, and signaling molecules. All proteins have a finite lifetime: they are synthesized and degraded continuously to maintain cellular function and viability. This continuous process is called "protein turnover." However, why is protein turnover important for cells? Even when the cells are in a basal state, the protein pool is dynamic and the coordination between protein synthesis and degradation maintains a steady-state level of proteins that is constantly renewed (2). Protein turnover is not only important to maintain protein concentrations in the cell, but also to allow for changes. Modulation of the proteome is necessary for most cellular responses, involving modifications in general or specific protein turnover (3,4). Neurons also have the ability to modulate and adjust their proteome in response to specific cues, for example, synaptic remodeling in response to patterns of action potentials in neurons.One complication of protein turnover in neurons is that synapses can be located up to hundreds of microns from the cell body. Where are proteins synthesized and degraded? Are proteins transported over the long distance from the soma to dendrites or axons, and if so, how do they reach their specific location within the intricate axonal and dendritic arbors. In fact, to overcome these challenges, neurons have very effective transport mechanisms to deliver proteins to remote regions of axons or dendrites; this has been recently reviewed in Refs. 5 and 6. Moreover, some proteins, such as receptors or scaffolding proteins, are in continuous movement in and out of the synapse with rapid rates (reviewed in Refs. 7 and 8). In addition to protein movement, neurons use local translation and degradation in dendrites and axons, allowing for a fine-tuned local protein turnover. Here we present an overview focused on...

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E6AP in the Brain: One Protein, Dual Function, Multiple Diseases

Cited by 24 publications

References 115 publications

Angelman syndrome: review of clinical and molecular aspects

Angelman syndrome: review of clinical and molecular aspects

Epigenetic Regulation of UBE3A and Roles in Human Neurodevelopmental Disorders

The Regulation of Synaptic Protein Turnover

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