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Title page for ETD etd-03232018-135223

Type of Document Dissertation
Author Gibson, Chelsea Lynn
URN etd-03232018-135223
Title Neurodegeneration and Metabolomic Impact of Genetic Elimination of the Orphan Metallo Beta-Lactamase, SWIP-10/MBLAC1
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Eric Delpire Committee Chair
Bruce Carter Committee Member
David Miller Committee Member
John McLean Committee Member
Randy Blakely Committee Member
  • C. elegans
  • dopamine
  • glia
  • glutamate
  • excitotoxicity
  • neurodegeneration
Date of Defense 2018-03-20
Availability unrestricted
Glutamate (Glu) signaling plays a critical role in regulating neural excitability, thus supporting many behaviors. Perturbed Glu homeostasis in the brain is implicated in multiple psychiatric and neurodegenerative disorders including Parkinson’s disease, where theories implicate excitotoxic Glu signaling in dopamine (DA) neuron degeneration. Microscopy studies demonstrate that mutation to a glial expressed gene in C. elegans, swip-10, induces premature and progressive DA neuron degeneration typified by dystrophic dendritic processes, as well as shrunken and/or missing cell soma. DA neuron degeneration in swip-10 mutants is rescued by glial-specific expression of WT swip-10, and genetic studies implicate Glu signaling, Ca2+-permeable Glu receptors, intracellular Ca2+ signaling, and apoptotic cell death in swip-10 DA neurodegeneration. Like swip-10, the putative mammalian ortholog, Mblac1, encodes a protein containing a metallo beta-lactamase domain. To gain insight into the role of MBLAC1 in vivo, CRISPR/Cas9 methods were employed to generate a MBLAC1 knockout (KO) model. Using serum from MBLAC1 KO and WT mice, untargeted metabolomic analyses were performed to nominate metabolic pathways responsive to MBLAC1 loss. Findings point to taurine metabolism, primary bile acid biosynthesis, and linoleate metabolism as pathways sensitive to loss of MBLAC1. The swip-10/MBLAC1 KO models serve as platforms for the elucidation of mechanisms that enhance risk for neurodegenerative diseases and/or the identification of agents that can limit excitotoxicity.
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