Autism-associated δ-catenin G34S mutation promotes GSK3β-mediated premature δ-catenin degradation inducing neuronal dysfunction
Date
2019
Authors
Nip, Kaila, author
Kim, Seonil, advisor
Bamburg, James, committee member
Tsunoda, Susan, committee member
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Abstract
δ-catenin is a crucial component of a synaptic scaffolding complex, which regulates synaptic structure and function in neurons. Loss of δ-catenin function is strongly associated with severe autism spectrum disorder (ASD) in female-enriched multiple families. In particular, a G34S (Glycine 34 to Serine) mutation in the δ-catenin gene has been identified in ASD patients and suggested to exhibit loss-of-function. The G34S mutation is located in the amino terminal region of δ-catenin, where there are no known protein interaction domains and post-translational modifications. Notably, the Group-based Prediction System predicts that the G34S mutation is an additional target for GSK3β-mediated phosphorylation, which may result in protein degradation. Therefore, we hypothesize the G34S mutation accelerates δ-catenin degradation, resulting in loss of δ-catenin function in ASD. Indeed, we found significantly lower G34S δ-catenin levels compared to wild-type (WT) δ-catenin when expressed in cells lacking endogenous δ-catenin, which is rescued by genetic inhibition of GSK3β. By using Ca2+ imaging in cultured mouse hippocampal neurons, we further revealed overexpression of WT δ-catenin is able to significantly increase neuronal Ca2+ activity. Conversely, Ca2+ activity remains unaffected in G34S δ-catenin overexpression, which is reversed by pharmacological inhibition of GSK3β using lithium. This suggests the G34S mutation of δ-catenin provides an additional GSK3β-mediated phosphorylation site, which could promote δ-catenin premature degradation, resulting in loss-of-function effects on neuronal Ca2+ activity in ASD. In addition, inhibition of GSK3β activity is able to reverse G34S-induced loss of δ-catenin function. Thus, inhibition of GSK3β may be a potential therapeutic treatment for δ-catenin-associated ASD patients.
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Subject
delta-catenin
autism
GSK3β