Abstract
Glutathione (GSH) is a tripeptide consisting of glutamate, cysteine, and glycine; it has a variety of functions in the central nervous system. Brain GSH depletion is considered a preclinical sign in age-related neurodegenerative diseases, and it promotes the subsequent processes toward neurotoxicity. A neuroprotective mechanism accomplished by increasing GSH synthesis could be a promising approach in the treatment of neurodegenerative diseases. In neurons, cysteine is the rate-limiting substrate for GSH synthesis. Excitatory amino acid carrier 1 (EAAC1) is a neuronal cysteine/glutamate transporter in the brain. EAAC1 translocation to the plasma membrane promotes cysteine uptake, leading to GSH synthesis, while being negatively regulated by glutamate transport associated protein 3-18 (GTRAP3-18). Our recent studies have suggested GTRAP3-18 as an inhibitory factor for neuronal GSH synthesis. Inhibiting GTRAP3-18 function is an endogenous mechanism to increase neuron-specific GSH synthesis in the brain. This review gives an overview of EAAC1-mediated GSH synthesis, and its regulatory mechanisms by GTRAP3-18 in the brain, and a potential approach against neurodegeneration.
Highlights
The brain is vulnerable to oxidative stress because of its high demand for oxygen, abundant unsaturated fatty acids that are targets of lipid peroxidation, and lower antioxidant enzyme activitiesInt
Catalase can remove only H2O2, but not hydroperoxides [21]. These results indicate that neurons are more vulnerable to oxidative stress than are glial cells in the brain, leading to neurodegeneration
GTRAP3-18−/− and wild-type mice, but those of cysteine and GSH in the brain were significantly higher in the GTRAP3-18−/− mice compared to the wild-type mice. These results indicate that the ability of Excitatory amino acid carrier 1 (EAAC1) to increase cysteine uptake for GSH synthesis is potentiated in GTRAP3-18−/−
Summary
The brain is vulnerable to oxidative stress because of its high demand for oxygen, abundant unsaturated fatty acids that are targets of lipid peroxidation, and lower antioxidant enzyme activities. Antioxidant mechanisms function efficiently in the brain to overwhelm the lethal insults to neurons by reactive oxygen species (ROS). Previous studies focused on the enzymatic regulation of GSH synthesis, and the regulatory mechanisms for the neuronal transport system of the rate-limiting substrate, cysteine, have not been clarified. Our recent studies have helped reveal the regulatory mechanisms for cysteine uptake leading to neuronal GSH synthesis. We provide an overview of the key molecular mechanisms underlying cysteine uptake leading to increase neuronal.
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