The Sulfur/Glutamate Circuitry in the Neuroimmune System

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DESCRIPTION (provided by applicant): In brain, sulfur metabolism exemplifies the principle of metabolic cooperation and furnishes cells with four major reagents critical for methylation reactions (S-adenosylmethionine), antioxidant capacity (glutathione), signaling (H2S), and cell volume regulation (taurine). An important intermediate in sulfur metabolism is homocysteine, which at elevated levels, is correlated with several neurological and other disorders including Alzheimer's disease. The pathways for glutathione and taurine syntheses require metabolic integration between astrocytes and neurons and intersect with yet another major cycle in brain, the glutamate-glutamine cycle that underlies glutamatergic synaptic transmission. Coordinate dysregulation of redox homeostasis and glutamate clearance leading to oxidative stress and excitotoxicity respectively, is a common thread in the pathologies of several neurological disorders, including Alzheimer's disease. We have been elucidating the regulation of homocysteine-based redox homeostasis in our laboratory and propose to broaden these studies to examine the sulfur metabolic co-dependence of astrocytes and neurons and its modulation by external stimuli, viz. glutamate, beta amyloid (A¿), and volume change by addressing the following specific aims. (i) We will determine the mechanisms underlying A¿ effects on antioxidant and glutamate clearance capabilities and identify the thiol proteome that responds to A¿ stimulation. (ii) We will assess the effects of glutamate-based signaling on T cell function and the mechanism of T cell-derived cytokines on modulating astrocytic glutamate clearance. (iii) We will determine where taurine pools are located by live cell imaging using X-ray fluorescence microscopy, elucidate the pathway for its synthesis in astrocytes and neurons and determine how it is modulated by volume alteration and by glutamate. Our studies will address major gaps in our understanding of the links between glutamate-based signaling, taurine-based osmoregulation and sulfur trafficking in astrocytes in the context of neuroprotection with biomedical relevance to a range of pathologies from Alzheimer's disease to hyponatremia. PUBLIC HEALTH RELEVANCE: In brain, sulfur metabolism modulates antioxidant capacity and cell volume regulation and is intimately interlinked with glutamate-based signaling. We propose to study the metabolic interdependence between astrocytes, neurons and T cells in performing these critical functions under normal and neurotoxic conditions.