Glycosylation is the most common post-translational modification to proteins, involving the addition of chained sugars to regulate folding, localization and intermolecular interactions. Glycosylated proteins are most heavily concentrated on the extracellular side of cellular membranes, and most secreted proteins are glycosylated. Both of these glycoprotein classes are critical for cell-cell interactions, particularly during metazoan development. The nervous system is enriched for glycoproteins, and neurons appear dependent on glycosylation in the regulation of synapse structure and function. This thesis tests glycosylation roles at the synapse by analyses of two genes at the Drosophila neuromuscular junction (NMJ); mgat1 required to produce hybrid and complex glycan branches, and pmm2 required to produce all N-linked glycosylation. Loss of either gene results in defective synaptic glycosylation, and similarly overelaborated NMJ architecture and elevated neurotransmission. Moreover, both mutant conditions cause aberrant trans-synaptic signaling that normally directs the recruitment of synaptic proteins required for synaptogenesis and neurotransmission. Thus, synaptic glycosylation strongly modulates the trans-synaptic signaling that in turn drives the recruitment synaptic proteins that mediate of structural and functional synaptogenesis. This thesis produces a new genetic model for the heritable Congenital Disorders of Glycosylation (CDG) disease state CDG1a (a.k.a. PMM2-CDG), producing an avenue for the development of treatments and therapeutic interventions.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03162016-135935 |
| Date | 17 March 2016 |
| Creators | Parkinson, William Matthew |
| Contributors | Aurelio Galli, Kendal Broadie, Todd Graham, Donna Webb, Terry Page, Aurelio Galli, Kendal Broadie, Todd Graham, Donna Webb, Terry Page |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03162016-135935/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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