A Drosophilia Model of Amyotrophic Lateral Schlerosis

肌萎缩侧索硬化症的果蝇模型

• 批准号: 6760848
• 负责人: STEPHEN M JACKSON
• 金额: $ 18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6760848
• 关键词: Drosophilidae; amyotrophic lateral sclerosis; autosomal recessive trait; behavior test; biological signal transduction; cytoskeleton; degenerative motor system disease; disease /disorder onset; double stranded RNA; electrophysiology; gene expression; gene interaction; gene mutation; gene targeting; histopathology; immunocytochemistry; intracellular transport; laboratory rabbit; motor neurons; neurogenetics; neuromuscular system; peptides; phenotype; technology /technique development

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile onset ALS characterized by spasticity of limb and facial muscles resulting from degeneration of motor neurons in the central nervous system. A gene responsible for ALS2 disease has recently been cloned that encodes a protein (termed alsin) with domains suggestive of functions in cell signaling, intracellular trafficking, and cytoskeletal organization. To gain further insight into the normal biological function of this gene, we propose to create a model of this disorder in the fruit fly Drosophila melanogaster. The Drosophila ALS2 gene (DALS2) encodes a polypeptide with 23% amino acid identity (38% similarity) to the human alsin polypeptide and is broadly expressed in a variety of tissue types throughout development. We propose to generate mutations in DALS2 using gene-targeting and double stranded RNA interference methods. Resulting DALS2 mutants will be characterized for signs of progressive motor neuron dysfunction and defects in cell signaling, intracellular trafficking, and cytoskeletal assembly. Additionally, we will conduct screens for genetic modifiers of the DALS2 phenotypes to elucidate the biochemical pathways leading to neuronal dysfunction and death in this Drosophila ALS2 disease model. Results from this work should clarify the normal cellular role of the ALS2 gene and may reveal strategies for treatment of ALS disease.

描述（由申请人提供）：肌萎缩性脊髓侧索硬化症2（ALS2）是青少年发病的ALS的一种常染色体隐性遗传形式，其特征是中枢神经系统运动神经元变性导致的四肢和面部肌肉痉挛。最近克隆了一种导致 ALS2 疾病的基因，该基因编码一种蛋白质（称为 alsin），其结构域暗示细胞信号传导、细胞内运输和细胞骨架组织中的功能。为了进一步了解该基因的正常生物学功能，我们建议在果蝇果蝇中创建这种疾病的模型。果蝇 ALS2 基因 (DALS2) 编码与人 alsin 多肽具有 23% 氨基酸同一性（38% 相似性）的多肽，并在整个发育过程中在多种组织类型中广泛表达。我们建议使用基因靶向和双链 RNA 干扰方法在 DALS2 中产生突变。由此产生的 DALS2 突变体将出现进行性运动神经元功能障碍以及细胞信号传导、细胞内运输和细胞骨架组装缺陷的迹象。此外，我们将筛选 DALS2 表型的遗传修饰因子，以阐明导致果蝇 ALS2 疾病模型中神经元功能障碍和死亡的生化途径。这项工作的结果应该阐明 ALS2 基因的正常细胞作用，并可能揭示 ALS 疾病的治疗策略。