Glial loss of the metallo β-lactamase domain containing protein, SWIP-10, induces age- and glutamate-signaling dependent, dopamine neuron degeneration

Abstract

Across phylogeny, glutamate (Glu) signaling plays a critical role in regulating neural excitability, thus supporting many complex behaviors. Perturbed synaptic and extrasynaptic Glu homeostasis in the human brain has been implicated in multiple neuropsychiatric and neurodegenerative disorders including Parkinson’s disease, where theories suggest that excitotoxic insults may accelerate a naturally occurring process of dopamine (DA) neuron degeneration. In C. elegans, mutation of the glial expressed gene, swip-10, results in Glu-dependent DA neuron hyperexcitation that leads to elevated DA release, triggering DA signaling-dependent motor paralysis. Here, we demonstrate that swip-10 mutations induce premature and progressive DA neuron degeneration, with light and electron microscopy studies demonstrating the presence of dystrophic dendritic processes, as well as shrunken and/or missing cell soma. As with paralysis, DA neuron degeneration in swip-10 mutants is rescued by glial-specific, but not DA neuron-specific expression of wildtype swip-10, consistent with a cell non-autonomous mechanism. Genetic studies implicate the vesicular Glu transporter VGLU-3 and the cystine/Glu exchanger homolog AAT-1 as potential sources of Glu signaling supporting DA neuron degeneration. Degeneration can be significantly suppressed by mutations in the Ca2+ permeable Glu receptors, nmr-2 and glr-1, in genes that support intracellular Ca2+ signaling and Ca2+-dependent proteolysis, as well as genes involved in apoptotic cell death. Our studies suggest that Glu stimulation of nematode DA neurons in early larval stages, without the protective actions of SWIP-10, contributes to insults that ultimately drive DA neuron degeneration. The swip-10 model may provide an efficient platform for the identification of molecular mechanisms that enhance risk for Parkinson’s disease and/or the identification of agents that can limit neurodegenerative disease progression.

Temperature regulates synaptic subcellular specificity mediated by inhibitory glutamate signaling

“…Glutamate spillover plays physiological or pathological roles [ 104 – 107 ]. The loss of astrocyte-like VCSC glia or glutamate reuptake transporter GLT-1 can alter the animal escaping or exploration behavior [ 107 ].…”

“…The loss of astrocyte-like VCSC glia or glutamate reuptake transporter GLT-1 can alter the animal escaping or exploration behavior [ 107 ]. Increasing the extracellular level of glutamate may also result in neurotoxicity and degeneration [ 104 , 108 ]. Similar functions of glutamate present in mammals [ 105 , 106 ].…”

Global untargeted serum metabolomic analyses nominate metabolic pathways responsive to loss of expression of the orphan metallo β-lactamase, MBLAC1

“…Our previous studies in the model system C. elegans identified the gene swip-10 as a glial regulator of dopamine (DA) signaling, with genetic studies supportive of a function linked to modulation of extracellular glutamate (Glu) levels that can drive increased DA neuron excitability and elevated DA secretion, as well as DA neuron degeneration. 4, 5 Both SWIP-10 protein, and its putative mammalian ortholog, MBLAC1, contain a single metallo β-lactamase (MBL) domain. 4, 6 Supporting the hypothesis that both SWIP-10 and MBLAC1 proteins function as enzymes, the MBL domains of both proteins possess the core motif (HxHxDH) found in prokaryotic and eukaryotic metallo-hydrolases that supports the coordination of metal ions to allow water polarization and substrate hydrolysis.…”

The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models

“…A very interesting model for glial control of Ca 2+ -dependent neuronal degeneration has been recently described in C. elegans. Mutation of the swip-10 gene (with still unknown function) induced hyperexcitability and a progressive degeneration of dopaminergic neurons, which was suppressed only by glial (but not neuronal) expression of the wild-type swip-10 gene [102,103]. Dopaminergic neuron degeneration in swip-10 mutants was reduced in calreticulin (crt-1) mutants and in calpain (clp-1) mutants, suggesting that excessive Ca 2+ increases are involved in the process.…”

“…Dopaminergic neuron degeneration in swip-10 mutants was reduced in calreticulin (crt-1) mutants and in calpain (clp-1) mutants, suggesting that excessive Ca 2+ increases are involved in the process. In addition, neurodegeneration was also attenuated by mutations in glutamate vesicular and plasma membrane transporters (vglu-3 and aat-1), and by mutations in the Ca 2+ -permeable glutamate receptors nmr-2 (NMDA-type) and glr-1 (AMPA-type) present in dopaminergic neurons [103]. The data suggest a picture in which swip-10 mutation somehow perturbs glutamate transport in glial cells, leading to an increased activation of neuronal glutamate receptors, increased neuronal Ca 2+ signaling, and progressive neurodegeneration by apoptosis.…”