Exploring functional links between circadian clocks, neurodegeneration, and aging in Drosophila melanogaster Public Deposited

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  • Circadian clocks are endogenous molecular mechanisms that coordinate daily rhythms in gene expression, cellular activities, and physiological functions with external day/night cycles. Breakdown of circadian rhythms such as sleep/wake cycles is associated with the onset of several neurological diseases; however, it is not clear whether disruption of rhythms is a symptom or cause of neurodegeneration, or both. To address this important question, circadian rhythms were disrupted by both genetic and environmental manipulations in Drosophila mutants prone to neurodegeneration. This led to shortening of lifespan, premature accumulation of oxidative and nervous damage during aging, and overall decline in healthspan, suggesting that circadian clocks may be causally involved in neuroprotective pathways in aging Drosophila. Recent evidence suggests bidirectional relationships between circadian rhythms and aging. While disruption of the clock mechanism accelerates aging and age-related pathologies in mammals, output rhythms of sleep and hormonal fluctuations tend to deteriorate during aging in humans, rodents, and fruit flies. To understand whether this decay is caused by defects in the core transcriptional clock, or weakening of the clock output pathways, a comprehensive study on age-related changes in the behavioral and molecular circadian rhythms was conducted using the fruit fly as a model organism. Aging caused disruption of rest/activity patterns and lengthening of the free-running period of the circadian locomotor activity rhythm. Transcriptional oscillations of four genes involved in the clock mechanism, period, timeless, Par domain protein 1ε, and vrille, were significantly reduced in heads, but not in bodies of aging flies. It was further determined that reduced transcription of these genes is not caused by the deficient expression of their activators, encoded by Clock and cycle genes. Moreover, transcriptional activation by CLOCK-CYCLE complexes is impaired despite reduced levels of the PERIOD repressor protein in old flies. These data suggest that aging alters the properties of the core transcriptional clock in flies such that both the positive and the negative limbs of the clock are attenuated. In fruit flies, the protein CRYPTOCHROME (CRY) acts in a cell-autonomous manner to synchronize circadian oscillations with light-dark cycles. The oscillatory amplitude of CRY is significantly dampened in heads of old flies at both mRNA and protein levels. Rescue of CRY using the binary GAL4/UAS system in old flies significantly enhanced the dampened molecular oscillations of several clock genes, and also strengthened the locomotor activity rhythms. There was a remarkable extension of healthspan in flies with elevated CRY. Conversely, CRY deficient mutants accumulated greater oxidative damage and showed accelerated functional decline. Interestingly, rescue of CRY in central clock neurons alone was not sufficient to restore rest/activity rhythms or extend healthspan. These data suggest novel anti-aging functions of CRY and indicate that peripheral clocks play an active role in delaying behavioral and physiological aging. Taken together, research conducted for this dissertation is a first attempt to elucidate functional links between circadian clocks, neurodegeneration, and aging. While previous evidence linking these processes was of correlative nature, functional studies conducted in this dissertation demonstrate that disruption of circadian clocks causes neurodegeneration and aging. While aging disrupts circadian rhythms at the molecular and behavioral levels, restoration of these rhythms can delay aging and improve healthspan in Drosophila. Owing to the conserved nature of clocks, novel insights obtained from this research can illuminate future translational research aimed to extend human healthspan.
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