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

Frontiers in Molecular Neuroscience

卷:11

David J. Segal¹  Janine M. LaSalle⁴  Simon Jesse Lopez⁴ 

[1] Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA, United States;

[2] Department of Medical Immunology and Microbiology, University of California, Davis, Davis, CA, United States;

[3] Genome Center, University of California, Davis, Davis, CA, United States;

[4] Integrative Genetics and Genomics, University of California, Davis, Davis, CA, United States;

[5] MIND Institute, University of California, Davis, Davis, CA, United States;

关键词: neurodevelopment;    parental imprinting;    human genetics and genomics;    synapse;    Angelman syndrome;    autism (ASD);   

DOI  :  10.3389/fnmol.2018.00476

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown