Novel neurobiological roles of UBE3A

Sun, Jiandong; Baudry, Michel; Bi, Xiaoning

doi:10.18632/oncotarget.15105

Cited by 3 publications

(3 citation statements)

References 7 publications

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“…All these deficits and abnormalities can be ameliorated by the administration of the mTORC1 inhibitor Rapamycin and the mTORC2 activator A-443654 [207]. E6AP has been shown to modulate mTORC1 signaling by altering the levels of p18, a component of the Ragulator complex [208].…”

Section: The Therapeutic Interventions Of Downstream Effectorsmentioning

confidence: 99%

UBE3A: The Role in Autism Spectrum Disorders (ASDs) and a Potential Candidate for Biomarker Studies and Designing Therapeutic Strategies

Roy,

Amemasor,

Hussain

et al. 2023

Diseases

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Published reports from the CDC’s Autism and Development Disabilities Monitoring Networks have shown that an average of 1 in every 44 (2.3%) 8-year-old children were estimated to have ASD in 2018. Many of the ASDs exhibiting varying degrees of autism-like phenotypes have chromosomal anomalies in the Chr15q11–q13 region. Numerous potential candidate genes linked with ASD reside in this chromosomal segment. However, several clinical, in vivo, and in vitro studies selected one gene more frequently than others randomly and unbiasedly. This gene codes for UBE3A or Ubiquitin protein ligase E3A [also known as E6AP ubiquitin-protein ligase (E6AP)], an enzyme involved in the cellular degradation of proteins. This gene has been listed as one of the several genes with a high potential of causing ASD in the Autism Database. The gain of function mutations, triplication, or duplication in the UBE3A gene is also associated with ASDs like Angelman Syndrome (AS) and Dup15q Syndrome. The genetic imprinting of UBE3A in the brain and a preference for neuronal maternal-specific expression are the key features of various ASDs. Since the UBE3A gene is involved in two main important diseases associated with autism-like symptoms, there has been widespread research going on in understanding the link between this gene and autism. Additionally, since no universal methodology or mechanism exists for identifying UBE3A-mediated ASD, it continues to be challenging for neurobiologists, neuroscientists, and clinicians to design therapies or diagnostic tools. In this review, we focus on the structure and functional aspects of the UBE3A protein, discuss the primary relevance of the 15q11–q13 region in the cause of ASDs, and highlight the link between UBE3A and ASD. We try to broaden the knowledge of our readers by elaborating on the possible mechanisms underlying UBE3A-mediated ASDs, emphasizing the usage of UBE3A as a prospective biomarker in the preclinical diagnosis of ASDs and discuss the positive outcomes, advanced developments, and the hurdles in the field of therapeutic strategies against UBE3A-mediated ASDs. This review is novel as it lays a very detailed and comprehensive platform for one of the most important genes associated with diseases showing autistic-like symptoms. Additionally, this review also attempts to lay optimistic feedback on the possible steps for the diagnosis, prevention, and therapy of these UBE3A-mediated ASDs in the upcoming years.

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Section: The Therapeutic Interventions Of Downstream Effectorsmentioning

confidence: 99%

UBE3A: The Role in Autism Spectrum Disorders (ASDs) and a Potential Candidate for Biomarker Studies and Designing Therapeutic Strategies

Roy,

Amemasor,

Hussain

et al. 2023

Diseases

View full text Add to dashboard Cite

show abstract

“…The significance of the mTOR pathway in brain development and synaptic plasticity has been well established [ 96 , 150 ]. Hyperactivation of mTORC1 and hypoactivation of mTORC2 in UBE3A -deficient mice is apparently associated with motor dysfunction and deficits in LTP, fear conditioning and memory, which could be restored by the mTORC1 inhibitor Rapamycin as well as the mTORC2 activator A-443654 [ 151 ].…”

Section: Therapeutic Approaches To Target E6ap and Downstream Effementioning

confidence: 99%

The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders

Owais

Mishra

Kiyokawa

2020

Cancers

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The HECT (Homologous to the E6-AP Carboxyl Terminus)-family protein E6AP (E6-associated protein), encoded by the UBE3A gene, is a multifaceted ubiquitin ligase that controls diverse signaling pathways involved in cancer and neurological disorders. The oncogenic role of E6AP in papillomavirus-induced cancers is well known, with its action to trigger p53 degradation in complex with the E6 viral oncoprotein. However, the roles of E6AP in non-viral cancers remain poorly defined. It is well established that loss-of-function alterations of the UBE3A gene cause Angelman syndrome, a severe neurodevelopmental disorder with autosomal dominant inheritance modified by genomic imprinting on chromosome 15q. Moreover, excess dosage of the UBE3A gene markedly increases the penetrance of autism spectrum disorders, suggesting that the expression level of UBE3A must be regulated tightly within a physiologically tolerated range during brain development. In this review, current the knowledge about the substrates of E6AP-mediated ubiquitination and their functions in cancer and neurological disorders is discussed, alongside with the ongoing efforts to pharmacologically modulate this ubiquitin ligase as a promising therapeutic target.

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“…Decreased mTORC2 activity in AS mice was reversed by rapamycin, indicating that mTORC1 over-activation leads to reduced mTORC2 activity in AS mice. Increased mTORC1 could also increase Arc levels that stimulate AMPA receptor endocytosis leading to the LTP and learning deficits seen in AS mice (Sun et al, 2017). These demonstrate the importance of mTOR balance in AS, however the specific mechanistic link between UBE3A and mTOR and how it contributes to AS phenotypes is not yet understood.…”

Section: Synaptic Roles For Ube3amentioning

confidence: 99%

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

Lopez

Segal

LaSalle

2019

Front. Mol. Neurosci.

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UBE3A is an E3 ubiquitin ligase encoded by an imprinted gene whose maternal deletion or duplication leads to distinct neurodevelopment disorders Angelman and Dup15q syndromes. Despite the known genetic basis of disease, how changes in copy number of a ubiquitin ligase gene can have widespread impact in early brain development is poorly understood. Previous studies have identified a wide array of UBE3A functions, interaction partners, and ubiquitin targets, but no central pathway fully explains its critical role in neurodevelopment. Here, we review recent UBE3A studies that have begun to investigate mechanistic, cellular pathways and the genome-wide impacts of alterations in UBE3A expression levels to gain broader insight into how UBE3A affects the developing brain. These studies have revealed that UBE3A is a multifunctional protein with important nuclear and cytoplasmic regulatory functions that impact proteasome function, Wnt signaling, circadian rhythms, imprinted gene networks, and chromatin. Synaptic functions of UBE3A interact with light exposures and mTOR signaling and are most critical in GABAergic neurons. Understanding the genome-wide influences of UBE3A will help uncover its role in early brain development and ultimately lead to identification of key therapeutic targets for UBE3A-related neurodevelopmental disorders.

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Novel neurobiological roles of UBE3A

Cited by 3 publications

References 7 publications

UBE3A: The Role in Autism Spectrum Disorders (ASDs) and a Potential Candidate for Biomarker Studies and Designing Therapeutic Strategies

UBE3A: The Role in Autism Spectrum Disorders (ASDs) and a Potential Candidate for Biomarker Studies and Designing Therapeutic Strategies

The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders

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

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