Neuronal UBE3A substrates hold therapeutic potential for Angelman syndrome

• Published in: Current opinion in neurobiology Vol. 88; p. 102899
• Main Authors: Krzeski, Joseph C., Judson, Matthew C., Philpot, Benjamin D.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2024
• Subjects: Angelman Syndrome - genetics; Angelman Syndrome - therapy; Animals; Humans; Neurons - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0959-4388; 1873-6882; 1873-6882
• DOI: 10.1016/j.conb.2024.102899

Emerging therapies for Angelman syndrome, a severe neurodevelopmental disorder, are focused on restoring UBE3A gene expression in the brain. Further therapeutic opportunities may arise from a better understanding of how UBE3A gene products—both long and short isoforms of the ubiquitin ligase E3A (UBE3A)—function in neurons. Great strides have been made recently toward identifying ubiquitin substrates of UBE3A in vitro and in heterologous expression systems. From this work, a particularly close relationship between UBE3A and subunits of the 19S regulatory particle of the proteasome has become evident. We propose that further research cognizant of isoform-specific UBE3A functional roles will be instrumental in elucidating key UBE3A/substrate relationships within distinct neuronal compartments, lending to the discovery of novel therapeutic targets and valuable clinical biomarkers for the treatment of Angelman syndrome. •UBE3A substrates hold promise for the treatment of Angelman syndrome (AS).•Neuronal context is key to understanding AS-relevant UBE3A/substrate relationships.•Subcellular localization of UBE3A isoforms may influence substrate interactions.•Disruption of UBE3A/proteasome interactions could broadly impact brain function.