The Ubiquitin E3 Ligase UBE3A Regulates GRIPAP1 and PACSIN1 Proteins Linked to the Endocytic Recycling of AMPA Receptors

Authors

Laura Drebushenko, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
Natalya Belous, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
Fritz W. Lischka, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
Qiong Zhou, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
Ayse Malci, Center for Neuroscience Research, Children's National Medical Center, Washington, DC, USA.
Michael S. Sidorov, Center for Neuroscience Research, Children's National Medical Center, Washington, DC, USA.
Barrington Burnett, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
Martin L. Doughty, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.

Document Type

Journal Article

Publication Date

7-16-2025

Journal

Molecular and cellular biology

DOI

10.1080/10985549.2025.2470431

Keywords

AMPA receptor; GRIPAP1; PACSIN1; UBE3A; cortical neuron; human induced pluripotent stem cell; synapse; ubiquitin

Abstract

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by cognitive and language impairments, seizures, reduced or fragmented sleep, motor ataxia, and a characteristic happy affect. AS arises due to the neuronal loss of UBE3A, an E3 ligase that regulates protein abundance through the addition of lysine 48 (K48)-linked polyubiquitin chains to proteins targeted for degradation by the ubiquitin proteasome system (UPS). Using a dual SMAD inhibition protocol to derive cortical neurons from human induced pluripotent stem cells, we examined UBE3A deletion effects on the neuronal proteome by liquid chromatography tandem mass spectrometry (LC-MS/MS). LC-MS/MS identified 645 proteins differentially abundant between UBE3A knockout (KO) and isogenic UBE3A wild-type control cortical neurons. Proteins with increased abundance with UBE3A loss of function include GRIPAP1 and PACSIN1, synaptic proteins implicated in AMPA receptor recycling. We provide evidence UBE3A polyubiquitinates PACSIN1 and GRIPAP1 to regulate protein turnover, with potential implications for impaired activity-dependent synaptic plasticity observed in AS.

APA Citation

Drebushenko, Laura; Belous, Natalya; Lischka, Fritz W.; Zhou, Qiong; Malci, Ayse; Sidorov, Michael S.; Burnett, Barrington; and Doughty, Martin L., "The Ubiquitin E3 Ligase UBE3A Regulates GRIPAP1 and PACSIN1 Proteins Linked to the Endocytic Recycling of AMPA Receptors" (2025). GW Authored Works. Paper 7580.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/7580

Department

Pediatrics