Project 2: Disease Mechanisms in Frontotemporal Dementia Linked to C9orf72 Expans

项目2拉吉尔·图雷纳摘要 越来越多的人认识到RNA加工改变在广泛性肺炎的发病机制中起着至关重要的作用 一系列疾病，包括两种毁灭性的神经退行性疾病，额叶颞叶痴呆(FTD) 肌萎缩侧索硬化症(ALS)。2011年六核苷酸扩增的开创性发现 C9orf72基因作为家族性FTD和ALS的最常见原因显著改变了我们的观点 这些神经退行性疾病。这种扩张的致病机制尚不清楚， 然而，初步观察表明，要么是内源性C9orf72基因功能丧失，要么是 RNA毒性机制。后者最初在其他重复扩张性疾病中描述，对应于 一种或多种核糖核酸结合蛋白(S)被扩增的RNA截留，导致广泛的错误调控 核糖核酸的加工。在这个项目中，我们将描述模拟C9orf72功能丧失或 解开每种机制的相对贡献并识别动物模型的功能的毒性获得 社区迫切需要解决FTD和ALS问题。在第二种方法中，我们将使用 在这些模型小鼠和死后获得无偏向RNA图谱的ART测序方法 来自ALS和FTD患者的组织。定义一组描述疾病依赖性的RNA改变 分子签名是开发治疗策略的重要一步。尤其是， 建议的方法的组合将提供关键信息来评估安全性和 利用反义技术降低C9orf72表达的潜在治疗策略的针对性 诱导携带C9orf72六核苷酸扩展的RNA降解的寡核苷酸(ASO)。

PROJECT 2 LAGIER TOURENNE ABSTRACT RNA processing alterations are increasingly recognized to play a crucial role in the pathogenesis of a wide range of diseases including two devastating neurodegenerative conditions, frontal temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The seminal discovery in 2011 of a hexanucleotide expansion in the C9orf72 gene as the most common cause of familial FTD and ALS significantly changed our perspective of these neurodegenerative diseases. The pathogenic mechanisms of this expansion are not understood, however, with initial observations pointing to either a loss of function of the endogenous C9orf72 gene or an RNA toxicity mechanism. The later, initially described in other repeat-expansion diseases, corresponds to the sequestration of one or more RNA binding protein(s) by expanded RNAs leading to broad misregulation of RNA processing. In this project, we will characterize mice modeling either a loss of C9orf72 function or a toxic gain of function to unravel the relative contributions of each mechanism and identify animal models strongly needed by the community to tackle FTD and ALS. In a second approach, we will use state of the art methods in sequencing to obtain an unbiased RNA profile in these model mice and in post-mortem tissues from ALS and FTD patients. Defining a set of RNA alterations that delineate a disease-dependent molecular signature is an important step toward the development of therapeutic strategies. In particular, the combination of the proposed approaches will provide crucial information to evaluate the safety and pertinence of a potential therapeutic strategy to reduce C9orf72 expression using antisense oligonucleotides (ASOs) that induce degradation of RNAs carrying the C9orf72 hexanucleotide expansion.