Rutgers, The State University of New Jersey, Department of Genetics, Nelson Biological Laboratories , Room AB422, Piscataway, NJ 08854 , USA +1 732 445 2813 ; +1 732 445 6920 ;
Expert Opin Drug Discov. 2013 Dec;8(12):1503-13. doi: 10.1517/17460441.2013.849691. Epub 2013 Oct 23.
Although vertebrate model systems have obvious advantages in the study of human disease, invertebrate organisms have contributed enormously to this field as well. The conservation of genome structure and physiology among organisms poses unexpected peculiarities, and the redundancy in certain gene families or the presence of polymorphisms that can slightly alter gene expression can, in certain instances, bring invertebrate systems, such as Drosophila, closer to humans than mice and vice versa. This necessitates the analysis of disease pathways in multiple model organisms.
The author highlights findings from Drosophila models of neurodegenerative diseases that have occurred in the past few years. She also highlights and discusses various molecular, genetic and genomic tools used in flies, as well as methods for generating disease models. Finally, the author describes Drosophila models of Alzheimer's, Parkinson's tri-nucleotide repeat diseases, and Fragile X syndrome and summarizes insights in disease mechanisms that have been discovered directly in fly models.
Full genome genetic screens in Drosophila can lead to the rapid identification of drug target candidates that can be subsequently validated in a vertebrate system. In addition, the Drosophila models of neurodegeneration may often show disease phenotypes that are absent in equivalent mouse models. The author believes that the extensive contribution of Drosophila to both new disease drug target discovery, in addition to target validation, makes them indispensible to drug discovery and development.
尽管脊椎动物模型系统在研究人类疾病方面具有明显优势，但无脊椎动物在这一领域也做出了巨大贡献。在生物体内，基因组结构和生理学的保守性带来了意想不到的特殊性，某些基因家族的冗余或导致基因表达略有改变的多态性，在某些情况下，使无脊椎动物系统（如果蝇）比老鼠更接近人类，反之亦然。这就需要在多种模型生物中分析疾病途径。
作者重点介绍了过去几年中在神经退行性疾病的果蝇模型中发现的结果。她还强调并讨论了在果蝇中使用的各种分子、遗传和基因组工具，以及生成疾病模型的方法。最后，作者描述了阿尔茨海默病、帕金森病三核苷酸重复疾病和脆性 X 综合征的果蝇模型，并总结了直接在果蝇模型中发现的疾病机制的见解。
在果蝇中进行全基因组遗传筛选可以快速鉴定出候选药物靶点，然后可以在脊椎动物系统中进行验证。此外，神经退行性疾病的果蝇模型通常可能显示出在等效的小鼠模型中不存在的疾病表型。作者认为，果蝇在新药靶发现以及靶标验证方面的广泛贡献，使它们成为药物发现和开发不可或缺的一部分。
