The ubiquitin E3 ligase UBE3A regulates GRIPAP1 and PACSIN1 proteins linked to the endocytic recycling of AMPA receptors

Author:

Drebushenko Laura1,Belous Natalya1,Lishcka Fritz W.1,Zhou Qiong1,Malci Ayse2,Sidorov Michael S.2,Burnett Barrington1,Doughty Martin L1

Affiliation:

1. Uniformed Services University of the Health Sciences

2. Children’s National Medical Center

Abstract

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 GRIPAP1 and PACSIN1 to regulate their protein turnover, providing novel insight into the pathogenic mechanism underlying the disease.

Publisher

Research Square Platform LLC

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