Genetic Mechanisms of Motor Neuron Degeneration

肌萎缩性侧索硬化症（ALS）是一种由运动神经元进行性变性引起的致死性迟发性疾病。尽管在鉴定与遗传性ALS病例相关的基因方面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未知。对被诊断为ALS的患者缺乏有效的治疗方法，这进一步强调了旨在了解这种毁灭性疾病病因的研究的重要性。然而，由于缺乏简单的运动神经元变性实验室模型，对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。大多数果蝇基因是高度保守的，因此，据估计，75%以上的人类致病基因都有一个同源果蝇基因。此外，果蝇的神经肌肉系统相对简单，使其成为研究运动神经元退化遗传机制的理想模型。通过在果蝇中创造基因嵌合体，我们的研究使我们能够以精确的分辨率可视化单个运动神经元中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，并利用运动行为分析确定已识别突变体的运动功能障碍的病理基础。预计本项目将建立一种新的运动神经元退行性变的果蝇模型，这将大大扩展我们目前对ALS病因和发病机制的认识，并将进一步为未来的治疗研究提供新的基因靶点。

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.