Role of C9ORF72 in Amyotrophic Lateral Sclerosis – C9ORF72-ALS

Amyotrophic Lateral Sclerosis (ALS) is the third most common neurodegenerative disease in the western world, affecting 1 individual in 50,000 people. This devastating disease is characterized by degeneration of motor neurons leading to muscle wasting and weakness, ultimately resulting in paralysis and death of patients.

Recently, the most common genetic cause of ALS was identified as an expansion of CGGGGC repeats located within the first intron of the C9ORF72 gene. This mutation is pathogenic through different non-exclusive mechanisms. First, expanded GGGGCC repeats are translated into toxic DPR proteins in absence of any ATG start codon, through a yet unexplained and non-canonical mechanism of translation. Next, these expanded repeats also lead to decreased expression of the C9ORF72 protein. Currently, it is unclear which one of these mechanisms is the leading cause of motor neuron degeneration and death. Also, while mutation in the C9ORF72 gene is the most common cause of ALS, there is little, yet, known on the function of the C9ORF72 protein.

Our results indicate that one of the functions of C9ORF72 is to regulate autophagy, which is a catabolic cellular mechanism indispensable for neurons to eliminate aggregates of toxic proteins. Consequently, reduction of C9ORF72 expression in ALS patients leads to sub-optimal autophagy that sensibilizes neurons to a second stress, resulting in neuronal cell degeneration (Sellier et al., 2016). Importantly, our preliminary data indicate that this second stress is the translation of the expanded GGGGCC repeats into DPR proteins. Thus, we propose that a combination of both loss and gain of function underlies ALS (double hit model). In that project, we propose to better understand the function of the C9ORF72 protein and to explore further our double hit hypothesis, notably by developing novel cellular and animal models. Furthermore, we also propose to screen pharmacological compound libraries to identify drugs correcting the toxicity of the proteins translated from expanded GGGGCC repeats in absence of C9ORF72.

Overall, this proposal will help to better understand the pathogenic mechanisms underlying neuronal degeneration in ALS patients, but also will help to define novel and innovative biomarkers and therapeutical strategy for that devastating disease.