Deal Samantha L, Yamamoto Shinya
Program in Developmental Biology, Baylor College of Medicine, Houston, TX, United States.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
Front Genet. 2019 Jan 14;9:700. doi: 10.3389/fgene.2018.00700. eCollection 2018.
Neurodegeneration is characterized by progressive loss of neurons. Genetic and environmental factors both contribute to demise of neurons, leading to diverse devastating cognitive and motor disorders, including Alzheimer's and Parkinson's diseases in humans. Over the past few decades, the fruit fly, , has become an integral tool to understand the molecular, cellular and genetic mechanisms underlying neurodegeneration. Extensive tools and sophisticated technologies allow geneticists to identify and study evolutionarily conserved genes that are essential for neural maintenance. In this review, we will focus on a large-scale mosaic forward genetic screen on the fly X-chromosome that led to the identification of a number of essential genes that exhibit neurodegenerative phenotypes when mutated. Most genes identified from this screen are evolutionarily conserved and many have been linked to human diseases with neurological presentations. Systematic electrophysiological and ultrastructural characterization of mutant tissue in the context of the visual system, followed by a series of experiments to understand the mechanism of neurodegeneration in each mutant led to the discovery of novel molecular pathways that are required for neuronal integrity. Defects in mitochondrial function, lipid and iron metabolism, protein trafficking and autophagy are recurrent themes, suggesting that insults that eventually lead to neurodegeneration may converge on a set of evolutionarily conserved cellular processes. Insights from these studies have contributed to our understanding of known neurodegenerative diseases such as Leigh syndrome and Friedreich's ataxia and have also led to the identification of new human diseases. By discovering new genes required for neural maintenance in flies and working with clinicians to identify patients with deleterious variants in the orthologous human genes, biologists can play an active role in personalized medicine.
神经退行性变的特征是神经元的渐进性丧失。遗传和环境因素都导致神经元的死亡，从而引发各种毁灭性的认知和运动障碍，包括人类的阿尔茨海默病和帕金森病。在过去几十年里，果蝇已成为理解神经退行性变潜在分子、细胞和遗传机制的重要工具。广泛的工具和先进的技术使遗传学家能够识别和研究对神经维持至关重要的进化保守基因。在本综述中，我们将聚焦于果蝇X染色体上的大规模镶嵌正向遗传筛选，该筛选导致鉴定出许多在突变时表现出神经退行性表型的必需基因。从该筛选中鉴定出的大多数基因在进化上是保守的，并且许多基因已与具有神经学表现的人类疾病相关联。在视觉系统背景下对突变组织进行系统的电生理和超微结构表征，随后进行一系列实验以了解每个突变体中神经退行性变的机制，从而发现了神经元完整性所需的新分子途径。线粒体功能、脂质和铁代谢、蛋白质运输和自噬方面的缺陷是反复出现的主题，这表明最终导致神经退行性变的损伤可能汇聚于一组进化保守的细胞过程。这些研究的见解有助于我们理解已知的神经退行性疾病，如 Leigh 综合征和弗里德赖希共济失调，也导致了新的人类疾病的鉴定。通过在果蝇中发现神经维持所需的新基因，并与临床医生合作识别直系同源人类基因中具有有害变异的患者，生物学家可以在个性化医疗中发挥积极作用。
