NewMutALS

Identification and characterization of novel genetic mutations in Amyotrophic Lateral Sclerosis. Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease characterized by loss of upper and lower motor neurons causing skeletal muscle atrophy and paralysis. An expansion of GGGGCC (G4C2) repeats in the C9ORF72 gene is the most common cause of ALS. These repeats are pathogenic through translation into toxic DPR proteins and through impaired expression of the C9ORF72 protein. We previously found that decreased expression of C9ORF72 causes motor neuronal cell death in zebrafish (Ciura et al., 2013) and that C9ORF72 regulates autophagy (Sellier et al., 2016), a protein clearance mechanism essential for neurons. Our most recent data identify novel missense mutations in the C9ORF72 gene. These coding mutations are found in ALS patients but not in control cohorts or control exome database. Our preliminary results in transfected neuronal cells and injected zebrafish indicate that these mutants alter autophagy and cause neuronal cell death. These results are important as they identify novel genetic mutations that may be pathogenic in ALS. Furthermore, these data reinforce the importance of C9ORF72 in this devastating disease. Thus, it is now crucial to confirm these results and explore further the pathogenic importance of these mutations. Moreover, the relationship, if any exist, between these missense mutations and the G4C2 repeat expansion in C9ORF72 is unclear. Finally, there is no treatment for this devastating disease. Thus, we propose to: 1 - Develop state-of-the-art iPS cell and animal (zebrafish and mouse) models of C9ORF72 mutations. 2 - Explore by which mechanisms C9ORF72 mutations alter autophagy. 3 - Explore whether these mutations can help to clarify the pathogenic effect of the G4C2 expansion. 4 - Identify compounds correcting autophagy alterations due to C9ORF72 mutations. Overall, our proposal is highly innovative as it identify novel genetic mutations in ALS-FTD. Furthermore, our project will help to better understand the causes of ALS and open novel routes toward treatment for that devastating disease.