Unraveling the Roles of UBE3A in Neurodevelopment and Neurodegeneration

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2025 Mar 13

PMID 40076922

Authors

Xin Yang

Yu-Wen Alvin Huang

Affiliations

Soon will be listed here.

Abstract

The ubiquitin-protein ligase E3A (UBE3A, aka E6-AP), an E3 ligase belonging to the HECT family, plays crucial roles in the stability of various proteins through the proteasomal degradation system. Abnormal UBE3A activity is essential for the initiation and progression of several cancers. A gain of function and an overdosage of maternal UBE3A is associated with an increased risk of autism spectrum disorders. Conversely, a loss of function due to mutations, deletions, paternal duplications, or imprinting defects in neurons leads to Angelman syndrome. Emerging evidence suggests that abnormal UBE3A activity may also contribute to the development of various brain disorders, including schizophrenia, Huntington's disease, Parkinson's disease, and Alzheimer's disease, making UBE3A a protein of significant interest. However, research on UBE3A's functions in the brain has primarily focused on neurons due to the imprinting of UBE3A in mature neuronal cells, while being obscured in glia. This review outlines the expression of UBE3A in neurons and glial cells based on published studies, highlights newly identified patterns of UBE3A, such as its secretion, and emphasizes the involvement of UBE3A in neurodegenerative diseases. Furthermore, we summarize glial UBE3A and propose a model of bi-directional interactions between the neurons and glia mediated by UBE3A that underlies brain functions. Insights gained from this research could provide new avenues for therapeutic interventions targeting various brain disorders.

References

Luo Y, Yang Y, Yang C, Li C, Hu R, Geng W . UBE3A and MCM6 synergistically regulate the proliferation and migration of lung adenocarcinoma cells. FEBS Open Bio. 2023; 13(9):1756-1771. PMC: 10476561. DOI: 10.1002/2211-5463.13675. View

Huang H, Allen J, Mabb A, King I, Miriyala J, Taylor-Blake B . Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature. 2011; 481(7380):185-9. PMC: 3257422. DOI: 10.1038/nature10726. View

Silva-Santos S, van Woerden G, Bruinsma C, Mientjes E, Aghadavoud Jolfaei M, Distel B . Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model. J Clin Invest. 2015; 125(5):2069-76. PMC: 4463212. DOI: 10.1172/JCI80554. View

Sun J, Zhu G, Liu Y, Standley S, Ji A, Tunuguntla R . UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis. Cell Rep. 2015; 12(3):449-61. PMC: 4520703. DOI: 10.1016/j.celrep.2015.06.023. View

Chaudhary P, Proulx J, Park I . Ubiquitin-protein ligase E3A (UBE3A) mediation of viral infection and human diseases. Virus Res. 2023; 335:199191. PMC: 10430597. DOI: 10.1016/j.virusres.2023.199191. View

Xu X, Li C, Gao X, Xia K, Guo H, Li Y . Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders. Cell Res. 2017; 28(1):48-68. PMC: 5752837. DOI: 10.1038/cr.2017.132. View

Punt A, Judson M, Sidorov M, Williams B, Johnson N, Belder S . Molecular and behavioral consequences of Ube3a gene overdosage in mice. JCI Insight. 2022; 7(18). PMC: 9675564. DOI: 10.1172/jci.insight.158953. View

Vivanti G, Tao S, Lyall K, Robins D, Shea L . The prevalence and incidence of early-onset dementia among adults with autism spectrum disorder. Autism Res. 2021; 14(10):2189-2199. PMC: 8487995. DOI: 10.1002/aur.2590. View

Kurihara T, Asahi T, Sawamura N . Cereblon-mediated degradation of the amyloid precursor protein via the ubiquitin-proteasome pathway. Biochem Biophys Res Commun. 2020; 524(1):236-241. DOI: 10.1016/j.bbrc.2020.01.078. View

10.

Smith S, Zhou Y, Zhang G, Jin Z, Stoppel D, Anderson M . Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Sci Transl Med. 2011; 3(103):103ra97. PMC: 3356696. DOI: 10.1126/scitranslmed.3002627. View

11.

Zhang Y, Chen K, Sloan S, Bennett M, Scholze A, OKeeffe S . An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014; 34(36):11929-47. PMC: 4152602. DOI: 10.1523/JNEUROSCI.1860-14.2014. View

12.

Hope K, Ledoux M, Reiter L . Glial overexpression of Dube3a causes seizures and synaptic impairments in Drosophila concomitant with down regulation of the Na/K pump ATPα. Neurobiol Dis. 2017; 108:238-248. PMC: 5675773. DOI: 10.1016/j.nbd.2017.09.003. View

13.

Glessner J, Wang K, Cai G, Korvatska O, Kim C, Wood S . Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009; 459(7246):569-73. PMC: 2925224. DOI: 10.1038/nature07953. View

14.

Chen J, Liu K, Hu B, Li R, Xin W, Chen H . Enhancing myelin renewal reverses cognitive dysfunction in a murine model of Alzheimer's disease. Neuron. 2021; 109(14):2292-2307.e5. PMC: 8298291. DOI: 10.1016/j.neuron.2021.05.012. View

15.

Bekes M, Langley D, Crews C . PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022; 21(3):181-200. PMC: 8765495. DOI: 10.1038/s41573-021-00371-6. View

16.

Tomaic V, Banks L . Angelman syndrome-associated ubiquitin ligase UBE3A/E6AP mutants interfere with the proteolytic activity of the proteasome. Cell Death Dis. 2015; 6:e1625. PMC: 4669770. DOI: 10.1038/cddis.2014.572. View

17.

Filonova I, Trotter J, L Banko J, Weeber E . Activity-dependent changes in MAPK activation in the Angelman Syndrome mouse model. Learn Mem. 2014; 21(2):98-104. PMC: 3895224. DOI: 10.1101/lm.032375.113. View

18.

Singh B, Vatsa N, Nelson V, Kumar V, Kumar S, Mandal S . Azadiradione Restores Protein Quality Control and Ameliorates the Disease Pathogenesis in a Mouse Model of Huntington's Disease. Mol Neurobiol. 2018; 55(8):6337-6346. DOI: 10.1007/s12035-017-0853-3. View

19.

Dindot S, Christian S, Murphy W, Berent A, Panagoulias J, Schlafer A . An ASO therapy for Angelman syndrome that targets an evolutionarily conserved region at the start of the transcript. Sci Transl Med. 2023; 15(688):eabf4077. DOI: 10.1126/scitranslmed.abf4077. View

20.

Mulherkar S, Jana N . Loss of dopaminergic neurons and resulting behavioural deficits in mouse model of Angelman syndrome. Neurobiol Dis. 2010; 40(3):586-92. DOI: 10.1016/j.nbd.2010.08.002. View