Circadian Timekeeping, Oxidative Stress and Metabolism in ALS Models

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The goal of this proposal is to establish whether disruption of the circadian timekeeping plays a role in the altered metabolism and oxidative stress observed in amyotrophic lateral sclerosis (ALS). The circadian rhythm coordinates metabolism and behavior to recurring daily environmental changes like light/dark cycles and food availability. Molecular clocks found on almost every cell create cell-autonomous circadian rhythms. A group of neurons located in the suprachiasmatic nucleus (SCN) synchronizes this multitude of oscillators across brain regions and the entire body. Loss of circadian timekeeping has been associated with cellular and system-wide alterations in metabolism, redox homeostasis and inflammation. ALS or Lou Gehrig's disease is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Beyond progressive motor impairment, ALS patients suffer from major defects in energy metabolism. Moreover, mitochondrial dysfunction and increased oxidative stress have been documented in sporadic and familial ALS, as well as in ALS-animal models. ALS-astrocytes induce motor neuron death in co-culture models and actively determine disease progression in hSOD1-linked ALS-mice. Since astrocytes play a major role in the control of metabolism and antioxidant defenses in the central nervous system, altered circadian regulation of these processes could have major consequences for neuronal health. Our preliminary data show altered clock genes expression in two hSOD1-linked ALS-mouse models and altered synchronization of clock genes in primary ALS-astrocytes. The fitness advantage that circadian rhythm confers relies in the ability of the self-autonomous oscillators found in different cells to properly respond to phase-setting cues. Thus, the failure of ALS-astrocytes to properly respond to these cues can negatively impact neuronal function and viability. Despite the numerous examples in support of the strong link between redox metabolism and circadian rhythmicity, there is still sparse direct in vivo experimental evidence coupling the two processes to neurodegeneration. In this exploratory proposal we will focus on the following specific aims: Aim1. To determine the role of altered circadian timekeeping in redox homeostasis and antioxidant defenses in ALS-astrocytes. Aim2. To determine the role of altered clock genes expression in peripheral synchronization and circadian behavior in ALS-mouse models. The results will provide direct experimental evidence for a role of altered circadian timekeeping in astrocyte- mediated neurotoxicity. Moreover the data obtained will highlight a novel link between circadian timekeeping and motor neuron degeneration in ALS. Since circadian dyssynchrony can be rescued, the results obtained may contribute to lay the groundwork for disease-modifying interventions.