Elucidating the mechanism of mitochondrial quality control in Drosophila

 描述（由申请人提供）：神经退行性疾病影响大量人口，目前尚无治愈方法。许多神经退行性疾病，如帕金森氏病，已与线粒体功能障碍，这可能在疾病的发病和进展中具有致病作用。由于线粒体为细胞提供大部分化学能量，因此它们对于高能组织的正常功能至关重要， 神经元。线粒体在细胞中发挥正常作用时可能会受损，细胞必须能够随后主动靶向并破坏受损的线粒体，这一过程称为线粒体自噬。阐明线粒体自噬的机制将为研究人员提供潜在的治疗靶点，以减轻神经退行性疾病的症状和进展。两种蛋白质，PTEN诱导的推定激酶1（PINK1）和帕金，在帕金森病的早期遗传形式中经常发生突变。此外，它们还被证明参与线粒体自噬。虽然PINK1和Parkin的研究很重要，但关于线粒体质量控制的分子机制仍有许多未解之谜。为了了解这一过程在体内是如何工作的，该提案的作者开发了果蝇卵巢和幼虫大脑作为研究线粒体功能的模型。他们的长期目标是了解控制体内组织中线粒体质量控制的机制。为了实现这一目标，他们对果蝇基因clu进行了表征，发现它对线粒体功能至关重要。clu突变果蝇是雄性和雌性不育的、高度不协调的和短命的，并且在它们的飞行肌肉和生殖细胞中具有肿胀的线粒体。它们的线粒体遭受氧化损伤，它们产生的ATP量大大减少。这些表型中的许多与PINK1和parkin突变果蝇共享，并且他们发现clu与parkin基因相互作用。因此，研究人员假设Clu在PINK1和Parkin诱导的线粒体自噬中起着关键作用。他们的目标是确定缺乏Clu如何改变PINK1和Parkin功能，并确定缺乏Clu对线粒体自噬水平的影响。支持Clu参与靶向线粒体破坏的证据将代表该途径的新成员。从这里提出的研究中获得的知识将大大促进我们对线粒体质量控制如何调节的理解，这是调节神经元健康的重要过程。

 DESCRIPTION (provided by applicant): Neurodegenerative diseases affect a large amount of the population and currently have no cures. Many neurodegenerative diseases, such as Parkinson's disease, have been linked to mitochondrial malfunction, which may have a causative role in disease onset and progression. Because mitochondria supply most of the chemical energy for the cell, they are critical for the normal function of high-energy tissues such as neurons. Mitochondria can become damaged carrying out their normal role in the cell, and the cell must be able to subsequently actively target and destroy damaged mitochondria, a process called mitophagy. Elucidating the mechanism of mitophagy will give researchers potential therapeutic targets to alleviate the symptoms and progression of neurodegenerative disease. Two proteins, PTEN induced putative kinase 1 (PINK1) and Parkin, are frequently mutated in early onset inherited forms of Parkinson's disease. In addition, they have been shown to be involved in mitophagy. While studies of PINK1 and Parkin have been important, there are still many unanswered questions about the molecular mechanisms of mitochondrial quality control. To understand how this process works in vivo, the authors of this proposal have developed Drosophila ovary and larval brain as a model in which to study mitochondria function. Their long term goal is to understand the mechanisms that control mitochondrial quality control in tissues in vivo. To accomplish this, they have characterized the Drosophila gene clueless (clu), and found that it is critical for mitochondria function. clu mutant flies are male and femal sterile, highly uncoordinated and short-lived, and have swollen mitochondria in their flight muscle and germ cells. Their mitochondria suffer oxidative damage, and they make substantially reduced amounts of ATP. Many of these phenotypes are shared with PINK1 and parkin mutant flies and they have found clu genetically interacts with parkin. As a result, the researchers hypothesize that Clu plays a critical role in PINK1 and Parkin-induced mitophagy. Their Aim will determine how lack of Clu alters PINK1 and Parkin function and determine the effect of lack of Clu on the levels of mitophagy. Evidence supporting that Clu is involved in targeted mitochondrial destruction will represent a new member of the pathway. Knowledge gained from the research proposed here will significantly advance our understanding of how mitochondrial quality control is regulated, which is an important process for regulating neuronal health.