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

项目2 LAGIER TOURENNE RNA加工改变越来越多地被认为在广泛的肿瘤的发病机制中起着至关重要的作用。 一系列疾病，包括两种破坏性神经退行性疾病，额颞叶痴呆（FTD） 和肌萎缩侧索硬化症（ALS）。2011年的开创性发现， C9orf72基因作为家族性FTD和ALS最常见的病因， 这些神经退行性疾病。这种扩张的致病机制尚不清楚， 然而，最初的观察结果表明，内源性C9orf72基因功能丧失或 RNA毒性机制后者，最初在其他重复扩增疾病中描述，对应于 一种或多种RNA结合蛋白被扩增的RNA隔离，导致广泛的误调节 RNA加工在这个项目中，我们将描述小鼠模型的特点，无论是C9orf72功能的丧失， 毒性功能的获得，以阐明每种机制的相对贡献，并确定动物模型 社区迫切需要解决FTD和ALS。在第二种方法中，我们将使用 在这些模型小鼠中和死后， 来自ALS和FTD患者的组织。定义一组RNA改变，描述疾病依赖性 分子标记是开发治疗策略的重要一步。特别是 所提出的方法的组合将提供关键信息，以评估安全性和 使用反义寡核苷酸降低C9orf72表达的潜在治疗策略的相关性 在一些实施方案中，C9orf72是诱导携带C9orf72六核苷酸扩增的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.