Function of the oxidoreductase PYROXD1 in axon regeneration

项目摘要/摘要 通过轴突再生，神经元在损伤后恢复功能。这一保守而复杂的过程需要 多种细胞途径，包括支持线粒体功能和RNA加工。线粒体 功能与许多神经疾病有关，线粒体功能障碍有助于 氧化应激，衰老的标志。然而，氧化环境在轴突再生中的作用 没有被很好地刻画。氧化还原酶是一类不同类型的酶，调节氧化 神经元的环境。氧化还原酶PYROXD1对人类健康非常重要，PYROXD1的缺失 在未折叠的蛋白质反应中，通过RtcB破坏线粒体功能和RNA连接。我们发现 PYROXD1是轴突再生所必需的；然而，PYROXD1促进轴突再生的机制 再生是未知的。这一建议将阐明PYROXD1在轴突再生中的作用机制 独立的目标。在目标1中，PYROXD1在损伤过程中线粒体功能和轴突定位中的作用 将会被确定。线粒体是轴突再生的关键，而PYROXD1是正常生长所必需的 线粒体的功能。目的1建立PYROXD1与线粒体在轴突形成过程中的关系 并将在这一过程中检查一组具有临床意义的PYROXD1突变。在目标2中， PYROXD1的作用--RNA连接酶RtcB的保护作用将被阐明。RtcB通过一种新的方式抑制轴突再生 未折叠蛋白应答过程中的非规范胞质剪接机制。RtcB依赖于 铜，这种依赖性使其对氧化环境中的失活非常敏感。目标2将决定 RtcB对体内氧化还原环境的敏感性及其与PYROXD1、RtcB和RtcB之间的关系 未折叠的蛋白反应基因XBP-1在再生中的作用。完成此奖学金后，受训人员将拥有 在支持和协作的环境中接受了广泛的培训。该项目将促进实习生的 技术技能、批判性思维能力和独立为分子领域的学术生涯做准备 神经科学。这个项目的结果将阐明氧化环境，线粒体的重要性 功能，以及成功再生轴突的RNA处理。

Project Summary/Abstract Through axon regeneration, neurons restore function after injury. This conserved, complex process requires numerous cellular pathways including support of mitochondrial function and RNA processing. Mitochondria function is implicated in numerous neurological disorders, and dysfunction of mitochondria contributes to oxidative stress, a hallmark of aging. However, the role of the oxidative environment in axon regeneration has not been well characterized. Oxidoreductases are a diverse class of enzymes that regulate the oxidative environment of neurons. The oxidoreductase PYROXD1 is important for human health, and loss of PYROXD1 disrupts mitochondrial function and RNA-ligation by RtcB during the unfolded protein response. We found that PYROXD1 is necessary for axon regeneration; however, the mechanism by which PYROXD1 promotes regeneration is unknown. This proposal will elucidate the mechanism of PYROXD1 in axon regeneration in two independent aims. In Aim 1, the role of PYROXD1 in mitochondria function and localization in axons during injury will be determined. Mitochondria are critical for axon regeneration, and PYROXD1 is required for normal mitochondria function. Aim 1 will establish the relationship between PYROXD1 and mitochondria during axon regeneration, and will examine a suite of clinically-significant PYROXD1 mutations in this process. In Aim 2, the role of PYROXD1-protection of the RNA-ligase RtcB will be clarified. RtcB inhibits axon regeneration via a novel mechanism of non-canonical cytoplasmic splicing during the unfolded protein response. RtcB is dependent on copper, and this dependence makes it sensitive to inactivation in oxidative environments. Aim 2 will determine the sensitivity of RtcB to redox environment in vivo and define the relationship among PYROXD1, RtcB, and the unfolded protein response gene xbp-1 in regeneration. Upon completion of this fellowship, the trainee will have received extensive training in a supportive and collaborate environment. The project will further the trainee’s technical skills, critical thinking abilities, and independence in preparation for an academic career in molecular neuroscience. The results of this project will shed light on the importance of oxidative environment, mitochondria function, and RNA processing for successful axon regeneration.