Exploring the mitochondrial function of TSEN in neuronal development and maintenance

项目总结： 神经发育和神经退化过程之间的交集在许多神经疾病中得到越来越多的认识，包括神经发育和精神疾病，如精神分裂症。理解这两个看似不同的过程之间联系的分子基础有望为神经元发育和维持的逻辑和原理提供基本的见解。线粒体是一种动态而复杂的细胞器，在生物的许多方面都起着重要的作用，从能量产生和中间代谢到细胞凋亡和钙缓冲。在帕金森氏症等神经退行性疾病以及精神分裂症等怀疑具有神经发育和神经退行性成分的疾病中，早期就观察到线粒体功能障碍。线粒体功能障碍是如何在疾病过程中发生的，以及线粒体在神经元发育和维护中的确切作用尚不清楚。在这个项目中，我们打算检验这样的假设，即tRNA剪接内切酶(Tsen)复合体通过调节线粒体功能来影响神经元的发育和维持。Tsen基因突变与桥小脑发育不全(PCH)有关，PCH是一种罕见的先天性疾病，以神经发育缺陷和神经变性为特征。Tsen的分子功能和Tsen功能障碍对神经元发育或维持的细胞机制还知之甚少。基于令人信服的初步结果，我们假设Tsen复合体对核编码呼吸链组件(NRCC)mRNAs的代谢和/或翻译起关键调节作用，以维持线粒体功能。为了检验这一假设，我们建议实现两个具体目标。在目标1中，我们试图建立Tsen相关疾病发病机制的线粒体基础。在目标2中，我们打算确定Tsen复合体调节线粒体功能的分子机制。果蝇模型将在这个项目中得到广泛应用。我们的实验室在使用果蝇作为模型来剖析通常涉及调节神经系统发育和维护的细胞信号通路方面经验丰富，努力对神经发育和退行性疾病的发病机制获得新的见解。我们在研究线粒体在这些基本过程中的作用方面特别有经验。利用我们开发的技术和我们获得的专业知识，我们的目标是产生第一个体内证据，证明Tsen关键地调节线粒体功能。我们期望这项研究的结果将为未来以果蝇为模型的线粒体Tsen调控的机制研究奠定基础，这有望为理解和治疗其他具有类似线粒体病因的神经发育/退行性疾病提供信息。

Project Summary: An intersection between neural development and neurodegeneration processes is increasingly being recognized in many neurological diseases, including neurodevelopmental and psychiatric diseases such as schizophrenia. Understanding the molecular basis underlying the connection between these two seemingly disparate processes promises to provide fundamental insights into the logic and principles of neuronal development and maintenance. Mitochondria are dynamic and complex organelles with essential roles in many aspects of biology, from energy production and intermediary metabolism to apoptosis and Ca2+ buffering. Mitochondrial dysfunction has been observed early on in neurodegenerative diseases such as Parkinson’s disease and in diseases suspected to have both neurodevelopmental and neurodegenerative components such as schizophrenia. How mitochondrial dysfunction arises in the disease process, and the exact roles of mitochondria in neuronal development and maintenance are not well understood. In this project we propose to test the hypothesis that the tRNA Splicing Endonuclease (TSEN) complex acts through regulation of mitochondrial function to influence neuronal development and maintenance. Genetic mutations in TSEN have been linked to Pontocerebellar Hypoplasia (PCH), a rare congenital disorder characterized by neurodevelopmental deficits as well as neurodegeneration. The molecular function of TSEN and the cellular mechanism of TSEN dysfunction on neuronal development or maintenance are poorly understood. Based on compelling preliminary results, we hypothesize that the TSEN complex critically regulates the metabolism and/or translation of nuclear encoded respiratory chain component (nRCC) mRNAs to maintain mitochondrial function. To test this hypothesis, we propose to achieve two Specific Aims. In Aim 1, we seek to firmly establish the mitochondrial basis of TSEN-associated disease pathogenesis. In Aim 2, we intend to determine the molecular mechanisms by which the TSEN complex regulates mitochondrial function. Drosophila TSEN models will be extensively used in this project. Our lab is highly experienced in the use of Drosophila as a model to dissect cellular signaling pathways commonly involved in regulating nervous system development and maintenance, in an effort to gain novel insights into the pathogenesis of neural developmental and degenerative diseases. We are particularly experienced in studying the role of mitochondria in these fundamental processes. Using the techniques we have developed and the expertise we have acquired, we aim to generate the first in vivo evidence that TSEN critically regulates mitochondrial function. We anticipate that results from this study will set the stage for future mechanistic studies of TSEN regulation of mitochondria using Drosophila as a model, which promises to inform the understanding and treatment of other neural developmental/degenerative disorders with similar mitochondrial etiologies.