Role of circadian clocks in maintaining a healthy nervous system

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DESCRIPTION (provided by applicant): The long term objective of this research is to define molecular pathways by which the circadian clock regulates neuronal health. Circadian clocks are molecular feedback loops that generate daily cellular rhythms in the brain and various peripheral tissues. Disruption of the circadian clock has been implicated in neurological disorders but the underling mechanisms connecting the clock to neuronal health are not understood. We have recently shown that loss of the circadian clock in Drosophila dramatically increased accumulation of oxidatively damaged proteins, lipids peroxides, and caused neurodegenerative changes in the brain. Furthermore, we identified a daily rhythm in levels of reactive oxygen species (ROS), while ROS was constantly elevated in flies with a disrupted circadian clock. Molecular oxidative damage is a significant risk factor for age-related neurological disorders and glutathione (GSH) is a key antioxidant that protects neuronal cells against oxidative stress. Depleted GSH levels are found in a number of neurological disorders including schizophrenia, Parkinson's, and Alzheimer's diseases as well as in normal aging. To counteract neurological diseases, basic research is needed to understand mechanisms regulating GSH homeostasis. We obtained exciting preliminary data suggesting that GSH synthesis may be controlled by the circadian clock. We revealed a circadian rhythm in the expression of the catalytic (GCLc) and modulatory (GCLm) subunits of glutamate cysteine ligase (GCL), which is the rate-limiting enzyme in GSH biosynthesis, as well as daily rhythmic changes in GSH levels. These rhythms were abolished in flies with a genetically disrupted circadian clock and in older flies, whose circadian clock becomes impaired. We hypothesize that the circadian clock modulates GSH biosynthesis, and that temporal regulation of GSH homeostasis results in efficient prevention/repair of oxidative damage and protection of the nervous system. To test this hypothesis, we propose an interdisciplinary collaboration using the excellent model system Drosophila melanogaster. In aim 1, we will determine roles of circadian clocks in the regulation of glutathione biosynthesis in the brain. We will then explore functional links between rhythms in GSH biosynthesis and neuronal health in aim 2. Finally, in aim 3 we will determine the effect of an aging circadian clock on the GSH system and neuronal health. Public health significance: Insights obtained from this work may lead to novel strategies to avert neurodegeneration in aging humans, which is a critically important medical and societal issue. PUBLIC HEALTH RELEVANCE: Disruption of the biological (circadian) clock has been implicated in neurological disorders but the underling mechanisms connecting the clock to neuronal health are not understood. The proposed studies will determine how the clock regulates biosynthesis of glutathione, a key antioxidant that is depleted in many neurological disorders including schizophrenia, Parkinson's, and Alzheimer's diseases. Insights obtained from this work may lead to novel strategies to avert neurodegeneration in aging humans, which is a critically important medical and societal issue.