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.

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PROJECT 2: LAGIER-TOURENNE- PROJECT NARRATIVE The most frequent cause of two devastating neurodegenerative diseases amyotrophic lateral sclerosis (ALS) (also called Lou Gehrig's disease) and frontotemporal dementia (FTD) has recently been identified in the uncharacterized C9orf72 gene. We will use state of the art sequencing approaches to identify disease mechanisms and provide tools leveraging therapeutic strategies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Specialized Center (P50)
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University of California San Diego
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