The Convergence of Titin and Elongator in Amyotrophic Lateral Sclerosis

项目摘要 肌萎缩侧索硬化症(ALS)，一种严重破坏运动的致命神经退行性疾病 神经元及其支配的随意肌肉是最常见的运动神经元病。 核仁应激是肌萎缩侧索硬化症的潜在致病机制。 家族性和散发性的常见形式，触发运动神经元的退化。 这项提议描述了一项发现，即人类蛋白质组中最大的蛋白质Titin是 存在于运动神经元的核仁中，并试图证明它在这方面的功能 细胞器及其受Elongator复合体的调节汇聚在核仁上，作为 ALS的疾病发病机制。该提案包括三个目标。在第一个目标中，Titin的 神经元的存在将得到充分的表征，包括识别特定的中枢和 显示核仁的外周神经系统细胞类型。第二个目标将测试 假设由TTN编码的Titin是运动神经元动态平衡所必需的，并且Titin 功能障碍是肌萎缩侧索硬化症新的潜在致病机制。的用法 选择性消融运动神经元TTN的条件性基因敲除小鼠将作为 研究这一假说的有力方法。第三个目标是试图理解为什么 Elongator复合体中的突变与ALS相关，并假设Elongator可能 实际上，作为一种常见的潜在疾病机制，它调节着肌动蛋白的产生。老鼠在 运动神经元中Elongator蛋白1(Elp1)的选择性消融表现出严重的 运动功能受损，表明Elp1的丢失足以导致ALS 表型。这些鼠标再次为调查Elongator目标提供了一个强大的工具 调控不当是肌萎缩侧索硬化症的原因之一。实现所描述的具体目标将 极大地提高了我们对潜在的分子和细胞途径的理解 误入歧途加速肌萎缩侧索硬化症的发生和发展，并将为 开发有效的治疗方法来治疗这种疾病。

Project Summary Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that ravages motor neurons and the voluntary muscles they innervate, is the most common motor neuron disease. Nucleolar stress was recently identified as an underlying pathogenic mechanism in ALS, common to both familial and sporadic forms, that triggers the degeneration of motor neurons. This proposal describes the discovery that titin, the largest protein in the human proteome, is present in the nucleolus of motor neurons and seeks to demonstrate that its function in this organelle and its regulation by the Elongator complex converge on the nucleolus as a nexus of disease pathogenesis in ALS. The proposal includes three Aims. In the first aim, titin’s presence in neurons will be fully characterized including identification of the specific central and peripheral nervous system cell types that exhibit nucleolar. The second aim will test the hypothesis that titin, encoded by TTN, is required for motor neuron homeostasis and that titin dysfunction represents a novel underlying pathogenic mechanism in ALS. The use of a conditional knockout mouse where TTN is selectively ablated in motor neurons will serve as a powerful approach for investigating this hypothesis. The third aim seeks to understand why mutations in the Elongator complex are associated with ALS and posits that Elongator may actually regulate the production of titin as a common underlying mechanism of disease. Mice in which the Elongator protein 1 (Elp1) is selectively ablated in motor neurons exhibit severely compromised motor function, demonstrating that the loss of Elp1 is sufficient to arrive at an ALS phenotype. These mice again provide a powerful tool for investigating Elongator targets whose misregulation contribute to ALS. Accomplishment of the described specific aims will significantly advance our understanding of the underlying molecular and cellular pathways that go awry to precipitate the onset and progression of ALS and will identify new targets for the development of effective therapeutics to treat the disease.