Genetic Mechanisms of Motor Neuron Degeneration

描述(申请人提供)：运动神经元变性的遗传机制肌萎缩侧索硬化症(ALS)是一种由运动神经元进行性退化引起的致命的晚发性疾病。尽管在识别与遗传性肌萎缩侧索硬化症相关的基因方面已经取得了相当大的进展，但这种疾病的病因在很大程度上仍然不清楚。对被诊断为肌萎缩侧索硬化症的患者缺乏有效的治疗方法，进一步强调了针对这种毁灭性疾病的原因进行研究的重要性。然而，由于缺乏简单的运动神经元变性实验室模型，ALS致病基因的鉴定受到严重阻碍。果蝇在我们理解许多人类神经退行性疾病的发病机制方面发挥了重要作用。果蝇的大多数基因是高度保守的，因此，据估计，超过75%的人类致病基因都有同源的果蝇基因。此外，果蝇神经肌肉系统的相对简单使其成为研究运动神经元变性的遗传机制的理想模型。通过在果蝇中创建遗传马赛克，我们的研究使我们能够以精致的分辨率可视化单个运动神经元内有害突变的表型效应。该项目将识别与运动神经元退化相关的新基因，并通过运动行为分析确定已识别的突变体中运动功能障碍的病理基础。本项目有望建立一种新的果蝇运动神经元变性模型，将极大地扩展我们目前对ALS病因和发病机制的认识，并将为未来的治疗研究提供新的基因靶点。 公共卫生相关性：肌萎缩侧索硬化症(ALS)是一种毁灭性的神经退行性疾病，目前尚无治愈方法。这项拟议的项目将发现与运动神经元进行性退化有关的新基因，显著扩大我们目前对ALS病因和发病机制的理解。

DESCRIPTION (provided by applicant): Genetic Mechanisms of Motor Neuron Degeneration Amyotrophic lateral sclerosis (ALS) is a fatal late-onset disease caused by the progressive degeneration of motor neurons. Although there has been considerable progress in the identification of genes linked to inherited cases of ALS, the etiology of this disease remains largely unknown. The lack of effective therapeutic treatments for patients diagnosed with ALS further underscores the importance of research directed at understanding the causes of this devastating disease. However, the identification of causative genes of ALS has been severely hindered by the lack of a simple laboratory model of motor neuron degeneration. The fruit fly Drosophila has played an instrumental role in our understanding of the pathogenesis of many human neurodegenerative diseases. The majority of Drosophila genes are highly conserved and, as a consequence, it is estimated that there is a homologous Drosophila gene for over 75% of human disease-causing genes. Furthermore, the relative simplicity of its neuromuscular system makes Drosophila an ideal model to study the genetic mechanisms underlying motor neuron degeneration. By creating genetic mosaics in Drosophila, our research allows us to visualize, with exquisite resolution, the phenotypic effects of deleterious mutations within a single motor neuron. This project will identify novel genes linked to motor neuron degeneration and determine the pathological basis of motor dysfunction in identified mutants using motor behavior assays. It is expected that this project will establish a novel Drosophila model of motor neuron degeneration that will significantly expand our current understanding of the etiology and pathogenesis of ALS and will further provide novel gene targets for future therapeutic research. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no known cure. The proposed project will identify new genes linked to the progressive degeneration of motor neurons, significantly expanding our current understanding of the etiology and pathogenesis of ALS.