Understanding Frontotemporal Dementia Using Drosophila and iPSC Models

摘要 老龄化人口中的痴呆症在未来几年构成了一个重大的全球健康挑战。除了老年痴呆症 额颞叶痴呆（FTD）是由局灶性痴呆引起的另一种主要形式的早老性痴呆， 前额叶和/或颞叶的退化。FTD患者表现出性格、社会 行为或语言产生。目前，FTD的有效治疗仍然难以捉摸， 致病机制知之甚少。许多基因突变的鉴定， 与FTD的关联提供了一个令人兴奋的切入点。其中GGGGCC（G4 C2）重复扩增在第一位 C9 ORF 72的内含子是FTD最常见的原因。这种突变也是最常见的遗传原因， 肌萎缩侧索硬化症（ALS），进一步强调了了解神经毒性引起的重要性， 通过扩增的G4 C2重复序列和从正义和反义重复序列翻译的二肽重复序列（DPR）蛋白， RNA。在这个建议中，我们将利用果蝇的经典遗传学和尖端的 这些技术适用于从诱导多能干细胞（iPSC）分化的患者神经元， 鉴定和表征与C9 ORF 72-FTD/ALS相关疾病表型的有效遗传修饰剂。这些 机制研究将有助于了解参与这些疾病的分子途径，也可能揭示 治疗干预的潜在有效药物靶点。

ABSTRACT Dementia in aging populations poses a major global health challenge in years to come. In addition to Alzheimer’s disease (AD), frontotemporal dementia (FTD) is another major form of presenile dementia caused by focal degeneration of the prefrontal and/or temporal lobes. FTD patients show changes in personality, social behaviors, or language production. Currently, effective treatments for FTD still remain elusive and the underlying pathogenic mechanisms are poorly understood. The identification of many genes whose mutations are associated with FTD offers an exciting entry point. Among them a GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 is the most common cause of FTD. This mutation is also the most common genetic cause of amyotrophic lateral sclerosis (ALS), further highlighting the importance of understanding neurotoxicity caused by expanded G4C2 repeats and dipeptide repeat (DPR) proteins translated from both sense and antisense repeat RNAs. In this proposal, we will take advantage of both classical genetics of fruitfly Drosophila and cutting-edge techniques that are applicable to patient neurons differentiated from induced pluripotent stem cells (iPSCs) to identify and characterize potent genetic modifiers of disease phenotypes relevant to C9ORF72-FTD/ALS. These mechanistic studies will help understand molecular pathways involved in these disorders and may also reveal potential effective drug targets for therapeutic interventions.