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.
Main collaborations:
- 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)
| Name | Position | ORCID |
|---|
- Karen Gaudon, Isabelle Pénisson-Besnier, Brigitte Chabrol, Françoise Bouhour, Laurence Demay, et al.. Multiexon deletions account for 15% of Congenital Myasthenic Syndrome with RAPSN mutations after negative DNA Sequencing. Journal of Medical Genetics, 2010, 47 (12), pp.795. ⟨10.1136/jmg.2010.081034⟩. ⟨hal-00574007⟩
- A. Ben Ammar, F. Petit, N. Alexandri, K. Gaudon, Stéphanie Bauché, et al.. Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7. Journal of Neurology, 2010, 257 (5), pp.754-766. ⟨10.1007/s00415-009-5405-y⟩. ⟨hal-03864208⟩
- Valérie Risson, Laetitia Mazelin, Mila Roceri, Hervé Sanchez, Vincent Moncollin, et al.. Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy. Journal of Cell Biology, 2009, 187 (6), pp.859-874. ⟨10.1083/jcb.200903131⟩. ⟨hal-02126916⟩
- Caroline Huzé, Stéphanie Bauché, Pascale Richard, Frédéric Chevessier, Evelyne Goillot, et al.. Identification of an agrin mutation that causes congenital myasthenia and affects synapse function.. American Journal of Human Genetics, 2009, 85 (2), pp.155-67. ⟨10.1016/j.ajhg.2009.06.015⟩. ⟨inserm-00409064⟩
- P. Rigoard, K. Buffenoir, Stéphanie Bauché, M. Fares, J. Koenig, et al.. Modalités et outils d’observation de la jonction neuromusculaire. Neurochirurgie, 2009, 55, pp.S43-S48. ⟨10.1016/j.neuchi.2008.03.013⟩. ⟨hal-03863752⟩
- S. D’houtaud, E. Sztermer, K. Buffenoir, J.-P. Giot, M. Wager, et al.. Formation et régénération synaptique. Neurochirurgie, 2009, 55, pp.S49-S62. ⟨10.1016/j.neuchi.2008.03.014⟩. ⟨hal-03863711⟩
- P. Rigoard, Stéphanie Bauché, K. Buffenoir, J.-P. Giot, J.-P. Faure, et al.. Le support anatomique de la contraction musculaire. Neurochirurgie, 2009, 55, pp.S69-S82. ⟨10.1016/j.neuchi.2008.05.006⟩. ⟨hal-03863717⟩
- P. Rigoard, K. Buffenoir, M. Chaillou, M. Fares, L. da Costa, et al.. Existe-t-il un retentissement sur la jonction neuromusculaire de rat lors de lésions du système nerveux central ?. Neurochirurgie, 2009, 55, pp.S110-S123. ⟨10.1016/j.neuchi.2008.05.009⟩. ⟨hal-03863786⟩
- P. Rigoard, K. Buffenoir, Stéphanie Bauché, J.-P. Giot, J. Koenig, et al.. Organisation structurale, moléculaire, formation et maturation de la jonction neuromusculaire. Neurochirurgie, 2009, 55, pp.S34-S42. ⟨10.1016/j.neuchi.2008.03.012⟩. ⟨hal-03863763⟩
- P. Rigoard, K. Buffenoir, M. Wager, Stéphanie Bauché, J.-P. Giot, et al.. Architecture moléculaire du réticulum sarcoplasmique et son rôle dans le couplage excitation-contraction. Neurochirurgie, 2009, 55, pp.S83-S91. ⟨10.1016/j.neuchi.2008.05.007⟩. ⟨hal-03863756⟩
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