School of Natural Sciences, Bangor University, Bangor, Gwynedd, UK.
Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK.
J Neurosci Methods. 2019 May 1;319:77-88. doi: 10.1016/j.jneumeth.2019.01.001. Epub 2019 Jan 8.
Work spanning almost two decades using the fruit fly, Drosophila melanogaster, to study tau-mediated neurodegeneration has provided valuable and novel insights into the causes and mechanisms of tau-mediated toxicity and dysfunction in tauopathies such as Alzheimer's disease (AD). The fly has proven to be an excellent model for human diseases because of its cost efficiency, and the availability of powerful genetic tools for use in a comparatively less-complicated, but evolutionarily conserved, in vivo system. In this review, we provide a critical evaluation of the insights provided by fly models, highlighting both the advantages and limitations of the system. The fly has contributed to a greater understanding of the causes of tau abnormalities, the role of these abnormalities in mediating toxicity and/or dysfunction, and the nature of causative species mediating tau-toxicity. However, it is not possible to perfectly model all aspects of human degenerative diseases. What sets the fly apart from other animal models is its genetic tractability, which makes it highly amenable to overcoming experimental limitations. The explosion of genetic technology since the first fly disease models were established has translated into fly lines that allow for greater temporal control in restricting tau expression to single neuron types, and lines that can label and monitor the function of subcellular structures and components; thus, fly models offer an unprecedented view of the neurodegenerative process. Emerging genetic technology means that the fly provides an ever-evolving experimental platform for studying disease.
跨越近二十年的工作，使用果蝇来研究 tau 介导的神经退行性变，为 tau 介导的毒性和功能障碍的原因和机制提供了有价值的新见解，如阿尔茨海默病（AD）等 tau 病。由于其成本效益高，并且具有强大的遗传工具可用于相对简单但进化上保守的体内系统，因此该果蝇已被证明是人类疾病的优秀模型。在这篇综述中，我们对果蝇模型提供的见解进行了批判性评估，突出了该系统的优势和局限性。该果蝇为了解 tau 异常的原因、这些异常在介导毒性和/或功能障碍中的作用以及介导 tau 毒性的致病物种的性质提供了更多的认识。然而，不可能完美地模拟人类退行性疾病的所有方面。使果蝇与其他动物模型区分开来的是其遗传易处理性，这使其非常适合克服实验限制。自第一个果蝇疾病模型建立以来，遗传技术的爆炸式发展已经转化为可以更严格地限制单个神经元类型表达 tau 的果蝇系，以及可以标记和监测亚细胞结构和成分功能的果蝇系；因此，果蝇模型提供了对神经退行性过程的前所未有的了解。新兴的遗传技术意味着果蝇为研究疾病提供了一个不断发展的实验平台。
