Molecular Genetic Insight into Neurodegenerative Disease from Drosophila

神经退行性疾病是当今医疗保健面临的最大挑战之一。这种疾病对家庭是毁灭性的，是巨大的经济负担。这些疾病包括阿尔茨海默病、帕金森病以及临床和病理相关的疾病额颞叶痴呆（FTD）和肌萎缩侧索硬化（ALS）。尽管有巨大的医学进步，延长了寿命，退行性疾病仍然是可怕的，对健康的巨大影响。需要新的方法和创新的应用，以提供对这些疾病的生物学见解和治疗进展的基础。黑腹果蝇是一种具有与人类高度保守的生物学途径、复杂的大脑和神经系统以及用于基因和途径发现和操纵的一系列惊人的遗传和分子生物学方法的非凡模式生物。我们建议应用果蝇的力量来了解神经退行性疾病的基因和机制。我们目前的重点是ALS/FTD的遗传和生物学基础。ALS是一种破坏性的运动神经元疾病，可导致快速瘫痪和死亡。FTD是第二种最常见的痴呆症。果蝇研究已经为这些疾病的生物学机制提供了许多惊人的见解，但仍需要更多的基本见解。我们已经开发并将继续开发家族性疾病的模型。我们独特的跨学科方法从苍蝇模型开始，我们使用该模型通过对疾病毒性的修饰剂进行遗传学筛选来识别感兴趣的途径。然后，我们将果蝇的发现扩展到人类患者组织，哺乳动物细胞和培养的初级神经元，最终返回我们的体内苍蝇模型以获得详细的机制见解。除了遗传研究之外，我们目前计划使用果蝇来评估关键风险因素的影响，例如创伤性脑损伤和肠道微生物群，这些因素的影响可能很难或不可能在哺乳动物模型或细胞中进行询问。因此，从果蝇开始，我们的研究计划致力于为理解疾病提供新的途径，并为当今社会面临的神经退行性疾病的巨大负担提供治疗见解的基础。

Neurodegenerative disease is among the greatest unmet challenges being faced in healthcare today. Such disease is devastating to families and an enormous economic burden. These disorders include Alzheimer's disease, Parkinson's disease, and the clinically- and pathologically-related disorders frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Despite tremendous medical advances that have extended lifespan, degenerative disease remains formidable with a huge impact on healthspan. Novel approaches and innovative applications are needed to provide biological insight into these diseases and the foundation for therapeutic advances. Drosophila melanogaster is a remarkable model organism with biological pathways highly conserved to humans, a complex brain and nervous system, and a staggering array of genetic and molecular biological approaches for gene and pathway discovery and manipulation. We propose to apply the power of Drosophila to understand genes and mechanisms that underlie neurodegenerative disease. Our special current focus is on the genetic and biological underpinnings of ALS/FTD. ALS is a devastating motor neuron disease that leads to rapid paralysis and death. FTD is the second most common form of dementia. Drosophila research has already provided many striking insights into the biological mechanisms of these diseases, while more basic insights are still needed. We have developed, and will continue to develop, models for familial disease. Our unique, interdisciplinary approach launches from a fly model, which we use to identify pathways of interest by performing genetics screens for modifiers of the disease toxicity. We then extend the findings from Drosophila into human patient tissue, mammalian cells, and primary neurons in culture, ultimately returning our in vivo fly model for detailed mechanistic insight. In addition to genetic studies, we currently plan on using the fly to assess the impact of critical risk factors, such as traumatic brain damage and the gut microbiota, the impacts of which can be difficult, or impossible, to interrogate in mammalian models or cells. Thus, launching from Drosophila, our research program strives to provide novel avenues for the understanding of disease and the foundation for therapeutic insight toward the enormous burden of neurodegenerative disease facing society today.