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.
Highlights
Across phylogeny, the amino acid glutamate (Glu) plays multiple, important roles including contributions to protein synthesis, intermediary metabolism, and chemical neurotransmission [1,2,3,4]
We demonstrate that C. elegans glia limit progressive degeneration of dopamine (DA) neurons that arises in the context of mutation of the protein, SWIP-10, and that this degenerative process relies on Glu signaling, altered Ca2+ homeostasis and apoptotic pathway genes
Our findings reveal a novel molecular contributor to glial maintenance of DA neuron viability, provide a genetically-tractable example of Glu-dependent cell death, and encourage further evaluation of SWIP-10 linked pathways for mechanistic insights into neurodegenerative diseases and their treatment
Summary
The amino acid glutamate (Glu) plays multiple, important roles including contributions to protein synthesis, intermediary metabolism, and chemical neurotransmission [1,2,3,4]. Glu signals through both metabotropic receptors that initiate Gprotein coupled signaling [5,6,7] as well as ionotropic receptors that flux ions such as Na+ and Ca2+, altering membrane excitability [5, 8,9,10]. Excessive ionotropic Glu signaling in the mammalian brain has been implicated in a variety of brain disorders including addiction, schizophrenia, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD) [11,12,13,14], as well as the neuronal death that arises in the context of stroke and glioblastoma [15, 16]. Chronic hyper-activation of neurons by Glu, within physiological limits, can drive apoptotic mediated neural degeneration, if other genetic or environmental risk pathways are engaged [21,22,23]. Glu activation of Glu receptors can lead to prolonged alterations in intracellular Ca2+ homeostasis, driving Ca2+-dependent proteolysis and activation of apoptotic programs [24]
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