UBE3A stabilization of β-catenin preserves synaptic proteins essential for motor and cognitive functions in Angelman Syndrome.

backgroundUbiquitin protein ligase E3A (UBE3A) regulates signaling pathways associated with autism spectrum disorders (ASDs). As an E3 ligase, UBE3A ubiquitinates and promotes the degradation of proteins crucial for regulating synaptic plasticity and learning. Loss-of-function mutations in UBE3A result in Angelman Syndrome, while gain-of-function or duplications contribute to ASDs and Dup15q Syndrome.

methodsIn this study, we investigated the effects of UBE3A loss on β-catenin stabilization in iPSC-derived neurons. We examined behavioral phenotypes in the Angelman Syndrome mouse model following lithium-induced inhibition of glycogen synthase kinase-3β (GSK3β).

resultsUBE3A insufficiency mimics Angelman Syndrome, leading to reduced β-catenin protein levels. Pharmacological inhibition of glycogen synthase kinase-3β (GSK3β) normalized both cytosolic and nuclear β-catenin levels and induced β-catenin-dependent expression of brain-derived neurotrophic factor (BDNF) and synaptic proteins. In the well-established UBE3A exon 2 deletion mouse model of Angelman syndrome, the pharmacological inhibition of GSK3β with lithium improved deficits in contextual fear and motor learning. UBE3A physically interacts with β-catenin, and inhibition of GSK3β decreased the excessive turnover of synaptic proteins in a β-catenin-dependent manner in UBE3A-depleted iNs. LIMITATIONS: The study is focused solely on lithium treatment for the exon 2 deletion mouse model.

conclusionUBE3A regulates synaptic function by stabilizing β-catenin. GSK3β is overactive in AS, and precisely inhibiting GSK3β or stabilizing β-catenin represents a potential new therapeutic strategy for treating brain disorders, including Angelman Syndrome and autism spectrum disorders.