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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Oxidative stress induces overgrowth of the Drosophila neuromuscular junction
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Oxidative stress induces overgrowth of the Drosophila neuromuscular junction

机译：氧化应激诱导果蝇神经肌肉接头过度生长

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摘要

Synaptic terminals are known to expand and contract throughout an animal's life. The physiological constraints and demands that regulate appropriate synaptic growth and connectivity are currently poorly understood. In previous work, we identified a Drosophila model of lysosomal storage disease (LSD), spinster {spin), with larval neuromuscular synapse overgrowth. Here we identify a reactive oxygen species (ROS) burden in spin that may be attributable to previously identified lipofuscin deposition and lysosomal dysfunction, a cellular hallmark of LSD. Reducing ROS in spin mutants rescues synaptic overgrowth and electrophysiological deficits. Synapse overgrowth was also observed in mutants defective for protection from ROS and animals subjected to excessive ROS. ROS are known to stimulate JNK and fos signaling. Furthermore, JNK and fos in turn are known potent activators of synapse growth and function. Inhibiting JNK and fos activity in spin rescues synapse overgrowth and electrophysiological deficits. Similarly, inhibiting JNK, fos, and jun activity in animals with excessive oxidative stress rescues the overgrowth phenotype. These data suggest that ROS, via activation of the JNK signaling pathway, are a major regulator of synapse overgrowth. In LSD, increased autophagy contributes to lysosomal storage and, presumably, elevated levels of oxidative stress. In support of this suggestion, we report here that impaired autophagy function reverses synaptic overgrowth in spin. Our data describe a previously unexplored link between oxidative stress and synapse overgrowth via the JNK signaling pathway.
机译：已知突触末端在动物的整个生命中都会扩张和收缩。目前尚不清楚调节适当的突触生长和连通性的生理限制和要求。在以前的工作中，我们确定了果蝇溶酶体贮积病（LSD），棘突（spin）和幼虫神经肌肉突触过度生长的果蝇模型。在这里，我们确定了自旋中的活性氧（ROS）负担，这可能归因于先前确定的脂褐素沉积和溶酶体功能障碍（LSD的细胞标志）。减少自旋突变体中的ROS可拯救突触过度生长和电生理缺陷。突触过度生长也出现在不能保护ROS的突变体和遭受过量ROS的动物中。已知ROS可以刺激JNK和fos信号传导。此外，JNK和fos又是已知的突触生长和功能的有效激活剂。抑制自旋中的JNK和fos活性可挽救突触过度生长和电生理缺陷。同样，在具有过度氧化应激的动物中抑制JNK，fos和jun活性可以挽救过度生长的表型。这些数据表明，通过激活JNK信号通路，ROS是突触过度生长的主要调节剂。在LSD中，自噬的增加有助于溶酶体的储存，并可能导致氧化应激水平升高。为支持该建议，我们在此处报告自噬功能受损可逆转自旋中的突触过度生长。我们的数据描述了通过JNK信号通路在氧化应激和突触过度生长之间的先前未曾探索的联系。

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    Valerie J. Milton; Helen E. Jarrett; Kate Gowers; Salma Chalak; Laura Briggs; lain M. Robinson; Sean T. Sweeney;

  • 作者单位

    Department of Biology and Hull York Medical School, University of York, York YO10 5DD, United Kingdom;

    Peninsula College of Medicine and Dentistry, University of Exeter and University of Plymouth, Plymouth PL6 8BU, United Kingdom;

    Department of Biology and Hull York Medical School, University of York, York YO10 5DD, United Kingdom;

    Department of Biology and Hull York Medical School, University of York, York YO10 5DD, United Kingdom;

    Department of Biology and Hull York Medical School, University of York, York YO10 5DD, United Kingdom;

    Peninsula College of Medicine and Dentistry, University of Exeter and University of Plymouth, Plymouth PL6 8BU, United Kingdom;

    Department of Biology and Hull York Medical School, University of York, York YO10 5DD, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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