Neuromuscular Connectivity in health and diseases
Our laboratory aims to understand the cellular and molecular mechanisms underlying neuromuscular synapse assembly and maintenance in physiological and pathological conditions.
The Neuromuscular junction (NMJ) is the contact zone between motor neurons and skeletal muscles. This synapse drives the precise initiation and control of motion. Therefore, much of our behavior and wellness relies on the appropriate functioning of this specialised structure. Neuromuscular transmission deficiency occurs in a large array of rare human diseases including channelopathies, congenital or acquired myasthenia and amyotrophic lateral sclerosis. Most of these pathologies are untreatable and life threatening with devastating economic and societal consequences in terms of loss of quality of life and of the burden of disability. The patients display complex clinical phenotypes mainly characterized by a profound muscle weakness and loss of mobility.
We combine unbiased screens and a large array of functional assays including quantitative morphological imaging, behavioral analysis and electrophysiology using mouse models and/or human-derived specimens to explore the complexity of the trans-synaptic mechanisms controlling neuromuscular connectivity. Our overarching goal is to improve physiopathological knowledge that can be used not only for molecular diagnosis and genetic counselling of families affected with the diseases of interest, but also to design new targets of therapeutic interest.
To achieve this goal, our team is built on an organization that favors tight interactions between practicing neurologists from the Paris Est French reference center for neuromuscular diseases and researchers/research assistants together with a large network of national/international collaborations to share knowledge and expertise.
We defined three main aims of research:
1) Characterize the molecular determinants underlying NMJ assembly and maintenance (PI: Laure Strochlic/Julien Messéant).
We have recently identified a new trans-synaptic pathway at the NMJ and developed innovative tools using mouse genetics to dissect its molecular characteristics.
2) Understand how disruption of nerve/muscle communication leads to neuromuscular diseases such as myasthenia and amyotrophic lateral sclerosis (PI: Stéphanie Godard-Bauché/Gaelle Bruneteau).
Thanks to our clinical expertise and our national networks, we analyze the physiopathological mechanisms underlying the studied diseases in patients.
3) Modulate trans-synaptic function to restore appropriate synaptic connectivity in a pathological context as a basis for therapeutic interventions (PI: Bertrand Fontaine/Laure Strochlic).
We develop innovative pharmacological or genetic strategies that promote trans-synaptic communication and nerve/muscle attachment to mitigate NMJ disease symptoms to ultimately prevent or compensate the progression of the loss of motor function in neuromuscular diseases.
Key words: Neuromuscular Junction, Neuromuscular disorders, disease modeling mouse models, human derived specimens, quantitative imaging, therapeutic strategies.
- Rozen Le Panse and Sonia Berrih-Aknin (France)
- Arnaud Ferry (France)
- Cécile Martinat (France)
- Eric Krejci (France)
- Frédérique Charbonnier (France)
- Nathalie Sans and Mireille Montcouquiol (France)
- Laurent Schaeffer, NeuroMyoGene Institute, (France)
- Hanns Lochmüller, The Children’s Hospital of Eastern Ontario (Canada)
- Markus Ruëgg, Biozentrum (Switzerland)
- Anna Punga, Uppsala University, (Sweden)
Our main publications
- International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019;365 (6460):. doi: 10.1126/science.aav7188. PubMed PMID:31604244 PubMed Central PMC7241648.
- Guimarães-Costa, R, Niérat, MC, Rivals, I, Morélot-Panzini, C, Romero, NB, Menegaux, F et al.. Implanted Phrenic Stimulation Impairs Local Diaphragm Myofiber Reinnervation in Amyotrophic Lateral Sclerosis. Am J Respir Crit Care Med. 2019;200 (9):1183-1187. doi: 10.1164/rccm.201903-0653LE. PubMed PMID:31291123 .
- Guimarães-Costa, R, Similowski, T, Rivals, I, Morélot-Panzini, C, Nierat, MC, Bui, MT et al.. Human diaphragm atrophy in amyotrophic lateral sclerosis is not predicted by routine respiratory measures. Eur Respir J. 2019;53 (2):. doi: 10.1183/13993003.01749-2018. PubMed PMID:30523161 .
- Mayaux, J, Lambert, J, Morélot-Panzini, C, Gonzalez-Bermejo, J, Delemazure, J, Llontop, C et al.. Survival of amyotrophic lateral sclerosis patients after admission to the intensive care unit for acute respiratory failure: an observational cohort study. J Crit Care. 2019;50 :54-58. doi: 10.1016/j.jcrc.2018.11.007. PubMed PMID:30472526 .
- International Multiple Sclerosis Genetics Consortium. Electronic address: , International Multiple Sclerosis Genetics Consortium. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell. 2018;175 (6):1679-1687.e7. doi: 10.1016/j.cell.2018.09.049. PubMed PMID:30343897 PubMed Central PMC6269166.
- Bauché, S, Vellieux, G, Sternberg, D, Fontenille, MJ, De Bruyckere, E, Davoine, CS et al.. Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy. J Neurol. 2017;264 (8):1791-1803. doi: 10.1007/s00415-017-8569-x. PubMed PMID:28712002 .
- Messéant, J, Ezan, J, Delers, P, Glebov, K, Marchiol, C, Lager, F et al.. Wnt proteins contribute to neuromuscular junction formation through distinct signaling pathways. Development. 2017;144 (9):1712-1724. doi: 10.1242/dev.146167. PubMed PMID:28348167 .