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Autism-associated δ-catenin G34S mutation promotes GSK3β-mediated premature δ-catenin degradation inducing neuronal dysfunction

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dc.contributor.authorNip, Kaila, author
dc.contributor.authorKim, Seonil, advisor
dc.contributor.authorBamburg, James, committee member
dc.contributor.authorTsunoda, Susan, committee member
dc.date.accessioned2019-06-14T17:06:58Z
dc.date.available2021-06-10T17:06:51Z
dc.date.issued2019
dc.description.abstractδ-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.
dc.format.mediumborn digital
dc.format.mediummasters theses
dc.identifierNip_colostate_0053N_15464.pdf
dc.identifier.urihttps://hdl.handle.net/10217/195416
dc.languageEnglish
dc.language.isoeng
dc.publisherColorado State University. Libraries
dc.relation.ispartof2000-2019
dc.rightsCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.
dc.subjectdelta-catenin
dc.subjectautism
dc.subjectGSK3β
dc.titleAutism-associated δ-catenin G34S mutation promotes GSK3β-mediated premature δ-catenin degradation inducing neuronal dysfunction
dc.typeText
dcterms.embargo.expires2021-06-10
dcterms.embargo.terms2021-06-10
dcterms.rights.dplaThis Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).
thesis.degree.disciplineCell and Molecular Biology
thesis.degree.grantorColorado State University
thesis.degree.levelMasters
thesis.degree.nameMaster of Science (M.S.)

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