Loss of circadian clock accelerates aging in neurodegeneration-prone mutants.
Loss of circadian clock accelerates aging in neurodegeneration-prone mutants.
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DOI：
10.1016/j.nbd.2011.12.034
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发表时间：
2012-03
影响因子：
6.1
通讯作者：
Giebultowicz, Jadwiga M.
中科院分区：
文献类型：
--
作者：
Krishnan, Natraj;Rakshit, Kuntol;Chow, Eileen S.;Wentzell, Jill S.;Kretzschmar, Doris;Giebultowicz, Jadwiga M.
生物钟在分子、细胞、生理和行为过程中产生节律。最近的研究表明，时钟机制的破坏会加速哺乳动物的机体衰老和与年龄相关的病理。在许多神经系统疾病中都观察到昼夜节律受损；然而，尚不清楚节律丧失是神经退行性变的原因还是结果，或者两者兼而有之。为了解决这个重要问题，我们研究了昼夜节律破坏对表现出与时钟无关的神经退行性表型的黑腹果蝇突变体的影响。我们将时钟基因周期（per01）中废除昼夜节律的无效突变与羰基还原酶基因嗅探器（sni1）中的低等位突变结合起来，后者显示氧化应激诱导的神经变性。我们报告说，与单一突变体相比，sni1 突变体的昼夜节律被破坏显着缩短了它们的寿命。双突变体的寿命缩短与成人大脑中的空泡化所证明的神经元退化加速有关。此外，与年龄匹配的单突变果蝇相比，per01 sni1 果蝇的垂直运动能力显着受损，且羰基化蛋白的积累增加。每个功能的丧失不会影响 sni mRNA 的表达，表明这些基因通过独立的途径发挥作用，产生附加效应。最后，我们发现，per01 突变与另一个基因瑞士奶酪 (sws1) 中易发生神经退行性疾病的突变相结合，会加速大脑病理的发生，而该基因不通过氧化应激途径发挥作用。综上所述，我们的数据表明，period 基因可能与衰老果蝇的神经保护途径有关。
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.
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