Wednesday, February 5, 2025
2/5/2025
Project Summary Circadian rhythms are a critical component of behavioral and homeostatic function in nearly every organism on Earth, including humans. Neurological diseases such as Alzheimer's, Parkinson's, and epilepsy are often accompanied by disruptions in circadian rhythms. In turn, this can exacerbate neuropathology symptoms and worsen quality of life by causing insomnia, fragmented sleep, daytime hypersomnia, and perturbation of metabolism. In fact, the links between metabolism and circadian function are becoming increasingly apparent. Several components of the core molecular clock are redox sensitive or transcriptionally modified by metabolites like NADPH, and mitochondria are known to exhibit circadian rhythms. Drosophila are an excellent model organism in which to study circadian rhythms at behavioral, genetic, and neuronal level, possessing a vast genetic toolkit and highly standardized methodology for assaying rhythmicity. We recently established that the stable Drosophila model for mitochondrial diseases such as Maternally Inherited Leigh Syndrome, termed ATP6[1], exhibits profound arrhythmicity in sleep/wake behavioral patterns and in specific behaviors such as egg laying and eclosion under constant conditions, making it an excellent model system in which to study the mechanistic links between altered metabolism and circadian rhythms. Here, we propose to determine the mechanism by which mitochondrial disease leads to rhythm disruption by probing the molecular clock's transcription-translation feedback loop, examining the physiology of the circadian circuit at the neuronal level, and elucidating the consequences of perturbed bioenergetics and redox state. Importantly, we have also recently discovered a successful treatment for the neurological consequences of mitochondrial disease in the ketogenic diet, including significant improvement in rhythmicity. Therefore, we propose in Aim 2 to determine the scope and mechanism by which this dietary therapy improves circadian function by examining bioenergetics and physiology of neurons and glia, ion channel modulation in circadian neurons, altered gene expression in the circadian circuit, and effects on the core clock. Additionally, we have found via a preliminary genetic screen that disruption of glycolysis and of the Krebs Cycle also have a negative impact on circadian rhythms. For example, RNAi knockdown and classical null alleles of citrate synthase have extremely poor rhythmicity. We propose in Aim 3 to use the power of the Drosophila genetic toolkit to identify novel modulators of circadian function in critical metabolic pathways including glycolysis, the Krebs Cycle, ketone body and lipid metabolism, amino acid and neurotransmitter synthesis, and others. Overall, this project will contribute significantly to our understanding of the links between metabolism and circadian rhythms in health and neurological disease, as well as open new therapeutic avenues based on diet and metabolic targets.
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