Stage Master

We are seeking a Master-2 student to study the molecular and cellular mechanisms underlying a neurodegenerative genetic disease, Amyotrophic Lateral Sclerosis (ALS).

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 death of the patients in 3 to 5 years. The most common genetic cause of ALS is an expansion of GGGGCC (G4C2) repeats located in the C9ORF72 gene. These repeats are translated in toxic proteins, and lead to a decreased expression of the C9ORF72 protein. Our recent results indicate that C9ORF72 regulates autophagy, a catabolic process necessary to eliminate protein aggregates and altered organelles.

Importantly, we found that the C9ORF72 protein forms a stable complex with 2 other proteins, SMCR8 and WDR41 (Sellier et al., 2016). We produced and purified this protein complex from baculovirus-infected insect cells, and preliminary experiments indicate that this complex is amendable to structure resolution by Cryo-EM. Furthermore, we found that this complex modulates cell vesicle trafficking through direct interaction and regulation of the activity of a specific small GTPase. Thus, this master project would be to (1) produce and purify the C9ORF72 complex associated to its regulated small GTPase in baculovirus-infected SF2 cells and perform preliminary Cryo-EM test; and eventually (2) to study this interaction using a wide range of molecular and cellular approaches (clonage, cell culture and transfection, western blot, immunoprecipitation, immunofluorescence, super resolution microscopy, etc.). Overall, this proposal will help to better understand the cause of neuronal degeneration in ALS, in order to define therapeutic strategy and drug screening design for this devastating disease.

Publications of the group during the 5 past years include Freyermuth et al., Nature Communication 2016; Sellier et al., Neuron 2017; Sellier et al., Nature Communication 2018; Boivin et al., EMBO Journal 2020; Boivin et al., Neuron 2021. Our group is located in IGBMC (http://www.igbmc.fr/), a large public research laboratory comprising ~800 persons involved in 50 research groups and 12 technological platforms, including all core services essential to the present project (baculovirus production, protein purification, CRYO-EM, cell culture, super resolution microscopy, etc.).

Site Web de l'équipe : http://www.igbmc.fr/research/department/4/team/42/