Molecular Genetic Analysis of TORC1 and TORC2 Signaling in Neuronal Maintenance

描述(申请人提供)：模型生物的遗传学研究为神经发育提供了巨大的洞察力，并揭示了脊椎动物和无脊椎动物在控制神经系统模式和连接的基因和途径上惊人的相似之处。与神经发育相比，人们对各种分化的神经元在充分发育并整合到神经回路后帮助维持其完整性和功能的分子和细胞机制知之甚少。预计对模式生物中神经元维持的核心机制的阐明将为人类的类似过程提供信息，这些损害是各种神经退行性疾病的基础，如阿尔茨海默病和帕金森病，目前还没有有效的治疗方法。果蝇已经成为阐明指导线粒体质量控制的信号网络的一个很好的模型系统，线粒体质量控制是一个多方面的过程，包括分裂/融合动力学、运输和自噬(有丝分裂)。这种线粒体质量控制过程对于多巴胺能神经元的结构和功能完整性至关重要，多巴胺能神经元是帕金森病失去的细胞类型。我们最近的遗传学研究揭示了雷帕霉素信号复合体的保守靶点(TORC1和TORC2)在调节线粒体功能和维持多巴胺能神经元完整性方面的新作用，尽管矛盾的是TORC1和TORC2在这一过程中表现出相反的作用。这项建议的目标是利用果蝇可用的分子遗传学、基因组学、生化和细胞生物学工具来破译TORC1和TORC2在线粒体调节中的作用机制，以努力从分子角度了解线粒体异常是如何发生的，以及它如何在与年龄相关的神经退行性疾病中影响神经元的完整性。需要检验的假设是，TORC1和TORC2通过指导线粒体调控的不同方面在多巴胺能神经元的维持中发挥核心作用，其中TORC2调控线粒体的质量控制，而TORC1通过翻译调控调控线粒体呼吸链复合体的生物发生。Fly研究的关键发现将在患者衍生的基于多巴胺能神经元的疾病模型中得到验证。更好地理解这个项目中将要研究的基因的功能，将为将线粒体调节与神经元维持联系起来的基本机制提供新的见解。这最终将有助于治疗与线粒体功能障碍相关的一系列神经退行性疾病。

DESCRIPTION (provided by applicant): Genetic studies in model organisms have provided tremendous insights into neural development and revealed surprising similarities between vertebrates and invertebrates in the genes and pathways controlling the patterning and wiring of the nervous system. Compared to neural development, much less is known about the molecular and cellular mechanisms that help maintain the integrity and function of the diverse differentiated neurons after they are fully developed and integrated into neural circuits. It is expected that elucidation of the mechanisms central to neuronal maintenance in model organisms will inform similar processes in humans, impairments of which underlie various neurodegenerative conditions such as Alzheimers disease and Parkinsons diseases, for which there is currently no effective treatment. Drosophila has served as an excellent model system to elucidate the signaling network that directs mitochondrial quality control, a multifaceted process encompassing fission/fusion dynamics, transport, and autophagy (mitophagy). This mitochondrial quality control process is crucially important for the structural and functional integrity of dopaminergic neurons, the cell types that are lost to Parkinsons disease. Our recent genetic studies have revealed novel roles of the conserved target of rapamycin signaling complexes (TORC1 and TORC2) in regulating mitochondrial function and maintaining dopaminergic neuron integrity, although paradoxically TORC1 and TORC2 exhibit opposite effects in this process. The goal of this proposal is to use molecular genetic, genomic, biochemical, and cell biological tools available in Drosophila to decipher the mechanisms of action of TORC1 and TORC2 in mitochondrial regulation, in an effort to understand in molecular terms how mitochondrial abnormality arises and how it impacts neuronal integrity in age-related neurodegenerative disease conditions. The hypothesis to be tested is that TORC1 and TORC2 play central roles in dopaminergic neuron maintenance by directing distinct aspects of mitochondrial regulation, with TORC2 regulating mitochondrial quality control whereas TORC1 regulating mitochondrial respiratory chain complex biogenesis through translational regulation. Key findings from the fly studies will be validated in patient-derived, dopaminergic neuron-based disease models. Greater understanding of the functions of the genes to be studied in this project will provide novel insights into the fundamental mechanisms linking mitochondrial regulation to neuronal maintenance. This will ultimately contribute to the treatment of a host of neurodegenerative conditions associated with mitochondrial dysfunction.