Neurodegeneration and Metabolomic Impact of Genetic Elimination of the Orphan Metallo Beta-Lactamase, SWIP-10/MBLAC1
Gibson, Chelsea Lynn
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.