Molecular Genetic Analysis of TORC1 and TORC2 Signaling in Neuronal Maintenance

描述（由申请人提供）：模式生物的遗传研究为神经发育提供了巨大的见解，并揭示了脊椎动物和无脊椎动物在控制神经系统模式和线路的基因和途径方面的惊人相似性。与神经发育相比，我们对不同分化神经元在完全发育并融入神经回路后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，这些过程的损伤是各种神经退行性疾病（如阿尔茨海默病和帕金森病）的基础，目前尚无有效治疗方法。果蝇作为一个很好的模型系统来阐明指导线粒体质量控制的信号网络，这是一个多方面的过程，包括裂变/融合动力学、运输和自噬（mitophagy）。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中丢失的细胞类型。我们最近的遗传学研究揭示了雷帕霉素信号复合物的保守靶点（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。本研究的目标是利用果蝇中现有的分子遗传学、基因组学、生化和细胞生物学工具来破译TORC1和TORC2在线粒体调控中的作用机制，从而从分子角度理解线粒体异常是如何产生的，以及它如何影响与年龄相关的神经退行性疾病条件下的神经元完整性。待验证的假设是，TORC1和TORC2通过指导线粒体调节的不同方面，在多巴胺能神经元的维持中发挥核心作用，其中TORC2调节线粒体质量控制，而TORC1通过翻译调节线粒体呼吸链复合体的生物发生。苍蝇研究的关键发现将在患者来源的、基于多巴胺能神经元的疾病模型中得到验证。对该项目中研究的基因功能的进一步了解将为线粒体调节与神经元维持之间的基本机制提供新的见解。这将最终有助于治疗与线粒体功能障碍相关的许多神经退行性疾病。

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.