Ionotropic receptor stoichiometry: pathways and pathology – RESTOICH

Nicotinic acetylcholine receptors (AChRs) are ligand-gated ion channels (LGCI) important for synaptic transmission at the neuromuscular junction (NMJ) and in the brain. They consist in multimeric complexes with high diversity of sub-unit combinations. The different AChR subtypes have specific pharmacological and functional properties and their deregulation has been associated to pathological conditions. The control of AChR stoichiometry requires multiple steps, from subunit assembly in the endoplasmic reticulum to trafficking to the cell membrane. The regulation of these mechanisms is barely known; however, their dysfunction causes myasthenic syndromes, neuropsychiatric diseases and nicotinic addiction.
I decided to initiate a research program to identify new factors and mechanisms that control the composition of AChRs and to further investigate their involvement in neuromuscular diseases. Because AChRs have been extremely conserved during evolution, I propose to address this question first using the nematode C. elegans. Based on my recent discovery of the existence of an unforeseen AChR composition diversity at the NMJ of C. elegans, I developed an innovative genetic strategy to decipher the mechanisms controlling receptor stoichiometry. I will then test the evolutive conservation of these mechanisms using state-of-the-art gene editing of both muscle and neuronal human cell lines.
Furthermore, the systems that I developed also provide an efficient pipeline to analyze the impact of genetic polymorphisms identified in patients suffering neuromuscular and neuropsychiatric diseases. This part of the project will be critical for evaluation of genotype-phenotype correlations and for diagnostic purposes. Altogether, my multisystem strategy will provide a means to identify novel genes and mechanisms involved in LGCI assembly under normal and pathological conditions.