Molecular Genetic Analysis of TORC1 and TORC2 Signaling in Neuronal Maintenance

TORC1 和 TORC2 信号在神经元维护中的分子遗传学分析

基本信息

批准号：
9903463
负责人：
Bingwei Lu
金额：
$ 34.23万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903463
关键词：
Aging Biogenesis Biological Brain Diseases Brain Neoplasms C-terminal Cells Complex Data Disease Drosophila genus Event Excision Failure Functional disorder Funding Genes Genetic Genetic study Genomics Goals Growth Homeostasis Human Impairment In Vitro Investigation Knowledge Lead Light Link Maintenance Mammalian Cell Mammals Mediating Mediator of activation protein Mental disorders Messenger RNA Metabolic Metabolism Mitochondria Mitochondrial Proteins Modeling Modification Molecular Molecular Genetics Neurodegenerative Disorders Neurons Nuclear Outer Mitochondrial Membrane Parkinson Disease Pathogenesis Pathologic Pathway interactions Patients Phosphorylation Phosphotransferases Physiological Physiology Post-Translational Protein Processing Process Production Proteins Proteomics Proto-Oncogene Proteins c-akt Quality Control Regulation Respiratory Chain Ribosomes Shapes Signal Pathway Signal Transduction Sirolimus Stroke Structure Testing Therapeutic Translations Traumatic Brain Injury Yeasts age related neurodegeneration biochemical tools dopaminergic neuron fly genetic analysis in vivo insight mitochondrial autophagy mitochondrial dysfunction mitochondrial messenger RNA nervous system disorder neuroinflammation novel novel strategies parkin gene/protein proteostasis response socioeconomics ubiquitin-protein ligase

项目摘要

Project Summary Age-related neurodegenerative diseases such as Parkinson's disease (PD) impose tremendous socioeconomic burdens due to the lack of disease-modifying treatment options. Mitochondrial dysfunction is intimately linked to neurodegenerative diseases. How mitochondrial abnormalities arise and how they relate to other features of neurodegenerative diseases such as proteostasis failure, Ca2+ dyshomeostasis, and neuroinflammation are poorly understood. Dynamic control of the structure, function, and distribution of mitochondria is also essential for normal neuronal function, a requirement necessitated by the highly polarized shape and unique physiology of neurons. Despite intensive efforts, many fundamental questions remain regarding the mechanisms linking mitochondrial regulation to neuronal maintenance. Pten-induced kinase 1(PINK1) and Parkin (encoding an E3 ubiquitin ligase), two genes associated with familial PD, have defined a genetic pathway important for mitochondrial and neuronal maintenance in flies and mammals. Identification of this pathway offers a much-needed entry point to understand the regulation of mitochondrial function in response to neuronal activity and metabolic needs, and to decipher the mechanistic link between mitochondrial dysfunction and other pathological hallmarks of disease. Our genetic studies revealed that PINK1/Parkin directs an interconnected mitochondrial quality control (MQC) process important for the maintenance of dopaminergic (DA) neurons. The multifaceted MQC process encompasses translational control of respiratory chain complex (RCC) biogenesis, mitochondrial fission/fusion dynamics, transport, and removal of defective mitochondria by autophagy (mitophagy). In the past funding period we have shown that the conserved target of rapamycin complexes (TORC1 and TORC2) act as important mediators of PINK1-directed MQC. One exciting finding from our investigation is that the PINK1/mTORC2 pathway exerts translational control of nuclear encoded RCC (nRCC) mRNAs. The goal of this proposal is to move away from the status quo of mitophagy-centric focus of PINK1-directed MQC by focusing on the newly discovered translational control function of PINK1/mTORC2 signaling. We will use a unique combination of molecular genetic, genomic, cell biological, and biochemical tools, and move between in vivo fly models and in vitro induced DA neuron (iDN) models. Our central hypothesis is that PINK1/mTORC2 signaling regulates DA neuron function and survival through ribosome-associated co-translational quality control (RQC) of select nuclear-encoded mitochondrial mRNAs, thus mechanistically linking mitochondrial function to protein homeostasis. We propose to elucidate how the RQC pathway mediates the effects of PINK1/mTORC2 on mitochondrial regulation and DA neuron maintenance (Aim 1), and dissect the molecular mechanism of RQC regulation by PINK1/mTORC2 signaling in both Drosophila models and patient-derived iDN models (Aim 2). These studies will significantly advance our understanding of how PINK1/mTORC2 signaling regulates DA neuron homeostasis, shed light on the poorly understood phenomenon of neuronal vulnerability to RQC failure, and potentially lead to novel and rational therapy for PD and other neurological disease conditions.

项目概要帕金森病 (PD) 等与年龄相关的神经退行性疾病对社会经济造成巨大影响由于缺乏缓解疾病的治疗方案而造成的负担。线粒体功能障碍与以下因素密切相关神经退行性疾病。线粒体异常是如何产生的以及它们与线粒体其他特征的关系神经退行性疾病，如蛋白质稳态失败、Ca2+ 稳态失调和神经炎症等，治疗效果较差明白了。线粒体的结构、功能和分布的动态控制对于正常的生命活动也是至关重要的。神经元功能，这是神经元高度极化的形状和独特的生理学所必需的要求。尽管付出了巨大的努力，关于线粒体连接机制的许多基本问题仍然存在对神经元维持的调节。 Pten 诱导激酶 1(PINK1) 和 Parkin（编码 E3 泛素连接酶），与家族性 PD 相关的两个基因，定义了对线粒体和神经元重要的遗传途径苍蝇和哺乳动物的维护。对该途径的识别提供了一个急需的切入点来理解响应神经元活动和代谢需求而调节线粒体功能，并破译线粒体功能障碍与疾病的其他病理特征之间的机制联系。我们的基因研究揭示 PINK1/Parkin 指导相互关联的线粒体质量控制 (MQC) 过程，这对于维持多巴胺能（DA）神经元。多方面的 MQC 流程包括转化控制呼吸链复合体 (RCC) 生物发生、线粒体裂变/融合动力学、运输和去除自噬（线粒体自噬）导致线粒体缺陷。在过去的资助期间，我们已经表明，保守的雷帕霉素复合物（TORC1 和 TORC2）的靶标充当 PINK1 定向 MQC 的重要介质。一我们的研究令人兴奋的发现是 PINK1/mTORC2 通路对核细胞发挥翻译控制作用。编码 RCC (nRCC) mRNA。该提案的目标是摆脱以线粒体自噬为中心的现状通过关注新发现的 PINK1/mTORC2 翻译控制功能，重点关注 PINK1 定向 MQC 发信号。我们将使用分子遗传学、基因组、细胞生物学和生化工具的独特组合，并在体内果蝇模型和体外诱导 DA 神经元 (iDN) 模型之间移动。我们的中心假设是 PINK1/mTORC2 信号通过核糖体相关共翻译调节 DA 神经元功能和存活选择核编码线粒体 mRNA 的质量控制 (RQC)，从而机械地连接线粒体蛋白质稳态的功能。我们建议阐明 RQC 途径如何介导以下作用： PINK1/mTORC2 对线粒体调节和 DA 神经元维持（目标 1）的影响，并剖析分子果蝇模型和患者来源的 iDN 中 PINK1/mTORC2 信号传导调节 RQC 的机制模型（目标 2）。这些研究将显着增进我们对 PINK1/mTORC2 信号传导机制的理解调节 DA 神经元稳态，揭示神经元脆弱性这一鲜为人知的现象 RQC 失败，并可能导致针对 PD 和其他神经系统疾病的新颖且合理的治疗。