Systematic Analysis of Fly Models with Multiple Drivers Reveals Different Effects of Ataxin-1 and Huntingtin in Neuron Subtype-Specific Expression

The fruit fly, Drosophila melanogaster, is a commonly used model organism for neurodegenerative diseases. Its major advantages include a short lifespan and its susceptibility to manipulation using sophisticated genetic techniques. Here, we report the systematic comparison of fly models of two polyglutamine (polyQ) diseases. We induced expression of the normal and mutant forms of full-length Ataxin-1 and Huntingtin exon 1 in cholinergic, dopaminergic, and motor neurons, and glial cells using cell type-specific drivers. We systematically analyzed their effects based on multiple phenotypes: eclosion rate, lifespan, motor performance, and circadian rhythms of spontaneous activity. This systematic assay system enabled us to quantitatively evaluate and compare the functional disabilities of different genotypes. The results suggest different effects of Ataxin-1 and Huntingtin on specific types of neural cells during development and in adulthood. In addition, we confirmed the therapeutic effects of LiCl and butyrate using representative models. These results support the usefulness of this assay system for screening candidate chemical compounds that modify the pathologies of polyQ diseases.

黑腹果蝇（Drosophila melanogaster）是神经退行性疾病研究中常用的模式生物，其核心优势在于生命周期短暂，且易于通过精密遗传技术开展操作。本研究针对两种多聚谷氨酰胺（polyQ）疾病的果蝇模型开展系统性对比分析：我们借助细胞类型特异性驱动元件，在胆碱能神经元、多巴胺能神经元、运动神经元与胶质细胞中诱导全长野生型及突变型共济失调蛋白1（Ataxin-1）与亨廷顿蛋白外显子1的表达，并基于羽化率、生命周期、运动能力及自发活动的昼夜节律等多种表型，系统性分析了上述蛋白的作用效应。该系统性检测体系可实现对不同基因型个体功能缺陷的定量评估与对比，研究结果表明，共济失调蛋白1与亨廷顿蛋白在发育阶段及成年期对特定神经细胞类型的影响存在差异。此外，我们通过代表性模型验证了氯化锂（LiCl）与丁酸钠的治疗效果。上述结果证实了该检测体系在筛选可调控多聚谷氨酰胺疾病病理进程的候选化合物方面的应用价值。