Induced Pluripotent Stem Cells and Drosophila Models of C9ORF72-Related FTD/ALS

痴呆症是我们在21世纪面临的最大全球健康挑战之一。额颞叶痴呆 (FTD)是60岁以下人群中第二常见的痴呆症， 机制知之甚少。FTD和肌萎缩侧索硬化症（ALS），一种主要的运动 神经元疾病，共享许多临床，病理和遗传特征。快速识别一系列 导致FTD/ALS的基因为剖析共同的致病分子提供了令人兴奋的机会， 可能是治疗干预的有效靶点的途径。在这场灾难中，我们学习的最多的 FTD/ALS的常见遗传原因，C9 ORF 72基因中的GGGGCC重复扩增。这种遗传 突变可能通过多种机制引起疾病，包括二肽诱导的神经毒性（DPR） 通过重复相关的非AUG（RAN）翻译产生的蛋白质。为了研究这些不同的致病性 机制，我们利用果蝇遗传学的力量，包括遗传抑制因子， 不同FTD/ALS疾病基因的增强子。这些研究经常揭示完全出乎意料的分子 揭示致病机制和提出新的治疗靶点的途径。此外，皮质 从患者特异性诱导多能干细胞（iPSC）和人类患者脑分化的神经元 将使用组织作为补充方法。这种综合方法结合了遗传，细胞， 分子、电生理和生物信息学分析，将使我们能够做出重大贡献， 痴呆症的研究。

Dementia is one of the greatest global health challenges we face in the 21st century. Frontotemporal dementia (FTD) is the second most common form of dementia among people under the age of 60 and its pathogenic mechanisms are poorly understood. FTD and amyotrophic lateral sclerosis (ALS), a predominantly motor neuron disease, share many clinical, pathological, and genetic features. The rapid identification of an array of genes that cause FTD/ALS has opened exciting opportunities to dissect shared pathogenic molecular pathways that may be effective targets for therapeutic intervention. In this appalication, we study the most common genetic cause of FTD/ALS, a GGGGCC repeat expansion in the C9ORF72 gene. This genetic mutation may cause disease through multiple mechanisms, including neurotoxicity induced by dipeptide (DPR) proteins generated through repeat-associated non-AUG (RAN) translation. To study these diverse pathogenic mechanisms, we take advantage of the power of Drosophila genetics including genetic suppressors and enhancers of different FTD/ALS disease genes. Such studies often reveal totally unexpected molecular pathways that shed light on pathogenic mechanisms and suggest novel therapeutic targets. In addition, cortical neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs) and human patient brain tissues will be used as a complementary approach. This integrated approach—combining genetic, cellular, molecular, electrophysiological, and bioinformatics analyses—will enable us to make significant contributions to dementia research in the years to come.