Abstract
Glutathione (GSH) is a key antioxidant that plays an important neuroprotective role in the brain. Decreased GSH levels are associated with neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Here we show that a diurnal fluctuation of GSH levels is correlated with neuroprotective activity against oxidative stress in dopaminergic cells. In addition, we found that the cysteine transporter excitatory amino acid carrier 1 (EAAC1), which is involved in neuronal GSH synthesis, is negatively regulated by the microRNA miR-96-5p, which exhibits a diurnal rhythm. Blocking miR-96-5p by intracerebroventricular administration of an inhibitor increased the level of EAAC1 as well as that of GSH and had a neuroprotective effect against oxidative stress in the mouse substantia nigra. Our results suggest that the diurnal rhythm of miR-96-5p may play a role in neuroprotection by regulating neuronal GSH levels via EAAC1.
Highlights
Glutathione (GSH) is a key antioxidant that plays an important neuroprotective role in the brain
It was shown that BMAL1-deficient mice exhibit increased levels of reactive oxygen species (ROS) and accelerated ageing, suggesting that the circadian clock is involved in ROS regulation[12]
Similar results were obtained using HEK293 cells (Supplementary Fig. 4b,c), namely, the transfection of miR-96-5p inhibitor in HEK293 cells increased the cell viability, GSH level and excitatory amino acid carrier 1 (EAAC1) level 18 or 24 h after the serum shock when the GSH level and protective activity against oxidative stress were lowest. These results suggest that the miR96-5p inhibitor has a protective role for oxidative stress by increasing EAAC1 and GSH levels in cultured cells
Summary
Glutathione (GSH) is a key antioxidant that plays an important neuroprotective role in the brain. We show that a diurnal fluctuation of GSH levels is correlated with neuroprotective activity against oxidative stress in dopaminergic cells. We found that the cysteine transporter excitatory amino acid carrier 1 (EAAC1), which is involved in neuronal GSH synthesis, is negatively regulated by the microRNA miR-96-5p, which exhibits a diurnal rhythm. Our results suggest that the diurnal rhythm of miR-96-5p may play a role in neuroprotection by regulating neuronal GSH levels via EAAC1. Glutathione is an especially important antioxidant in the central nervous system because of the lower activity of major antioxidant enzymes such as superoxide dismutase and catalase in the brain[3] Glutathione exists in both a reduced form (GSH) and an oxidized form (GSSG), functioning in various redox reactions. The mechanism of this association has long been elusive,
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