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N-linked glycosylation is fundamentally linked to the surface expression of neuroligins

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dc.contributor.authorCast, Thomas, author
dc.contributor.authorChanda, Soham, advisor
dc.contributor.authorDeLuca, Jennifer, committee member
dc.contributor.authorDi Pietro, Santiago, committee member
dc.contributor.authorTobet, Stuart, committee member
dc.date.accessioned2023-08-28T10:29:14Z
dc.date.available2024-08-28T10:27:54Z
dc.date.issued2023
dc.description.abstractN-linked glycosylation is one of the most prevalent forms of post-translational modification, decorating secreted and cell-surface transmembrane proteins as they are trafficked along the secretory pathway. While well-characterized in most tissues, non-canonical N-glycan diversification has been reported to occur in the central nervous system. Chapter 2 of this dissertation describes the importance of N-linked glycosylation for the neuroligin family of synaptic cell-adhesion molecules (NLGN1-4). NLGNs play a crucial role in regulating synaptic transmission strength by recruiting neurotransmitter receptors to synapses. Mutation of N-glycosylated residues increased retention of each NLGN isoform in the endoplasmic reticulum (ER), consequentially reducing their ability to interact with presynapses. Pharmacological inhibition of various stages of the N-glycan maturation pathway further revealed that only the initial transfer of the polysaccharide is essential for the surface expression of NLGN proteins. Chapter 3 characterizes a missense mutation identified in the NLGN4 gene of a patient with autism. This mutation, p.Arg101Gln (R101Q), is directly upstream of a conserved N-linked glycosylation site, which played a universal role for the surface localization of each NLGN isoform. Biochemical and cellular analysis revealed the NLGN4-R101Q variant to be immaturely glycosylated and mistrafficked, retained in the ER similarly to N-glycan site mutants. In neurons, the mistrafficked R101Q variant failed to reproduce the excitatory synaptogenic effects of NLGN4-WT, indicating an overall loss-of-function phenotype. Further, equivalent RQ mutations introduced in other NLGN isoforms mimicked the glycoprotein maturation and surface expression defects. Together, these findings reveal a profound overall significance of N-glycans for NLGNs and the conserved role of a specific N-linked glycosylation site for promoting the forward trafficking of NLGN protein.
dc.format.mediumborn digital
dc.format.mediumdoctoral dissertations
dc.identifierCast_colostate_0053A_17824.pdf
dc.identifier.urihttps://hdl.handle.net/10217/237010
dc.languageEnglish
dc.language.isoeng
dc.publisherColorado State University. Libraries
dc.relation.ispartof2020-
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.subjectglycosylation
dc.subjectneuroligin
dc.subjecttrafficking
dc.subjectN-linked
dc.subjectautism
dc.subjectsynapse
dc.titleN-linked glycosylation is fundamentally linked to the surface expression of neuroligins
dc.typeText
dcterms.embargo.expires2024-08-28
dcterms.embargo.terms2024-08-28
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.disciplineBiochemistry and Molecular Biology
thesis.degree.grantorColorado State University
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)

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