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Loss of circadian clock accelerates aging in neurodegeneration-prone mutants

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https://ir.library.oregonstate.edu/concern/articles/2b88qd55c

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  • Circadian clocks generate rhythms in molecular, cellular, physiological, and behavioral processes. Recent studies suggest that disruption of the clock mechanism accelerates organismal senescence and age-related pathologies in mammals. Impaired circadian rhythms are observed in many neurological diseases; however, it is not clear whether loss of rhythms is the cause or result of neurodegeneration, or both. To address this important question, we examined the effects of circadian disruption in Drosophila melanogaster mutants that display clock-unrelated neurodegenerative phenotypes. We combined a null mutation in the clock gene period (per⁰¹) that abolishes circadian rhythms, with a hypomorphic mutation in the carbonyl reductase gene sniffer (sni¹), which displays oxidative stress induced neurodegeneration. We report that disruption of circadian rhythms in sni¹ mutants significantly reduces their lifespan compared to single mutants. Shortened lifespan in double mutants was coupled with accelerated neuronal degeneration evidenced by vacuolization in the adult brain. In addition, per⁰¹ sni¹ flies showed drastically impaired vertical mobility and increased accumulation of carbonylated proteins compared to age-matched single mutant flies. Loss of per function does not affect sni mRNA expression, suggesting that these genes act via independent pathways producing additive effects. Finally, we show that per⁰¹ mutation accelerates the onset of brain pathologies when combined with neurodegeneration-prone mutation in another gene, swiss cheese (sws¹), which does not operate through the oxidative stress pathway. Taken together, our data suggest that the period gene may be causally involved in neuroprotective pathways in aging Drosophila.
  • This is the authors' peer reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Elsevier and can be found here: http://www.journals.elsevier.com/neurobiology-of-disease/#description
  • Keywords: RING assay, circadian rhythms, biological clock, protein carbonyls, neuronal health
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  • Krishnan, Natraj, Rakshit, Kuntol, Chow, Eileen S., Wentzell, Jill S., Kretzschmar, Doris, Giebultowicz, Jadwiga M., Loss of circadian clock accelerates aging in neurodegeneration-prone mutants, Neurobiology of Disease (2011), doi: 10.1016/j.nbd.2011.12.034
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  • 45
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  • 3
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  • This research was supported in part by NIH R21AG038989 and R21 NS075500 grants to JMG and R01 NS047663 to DK. KR is supported by NSF IGERT in Aging Sciences Fellowship at OSU (DGE 0965820).
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