Co-team leaders: Bertrand Fontaine & Laure Strochlic
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
- 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.
- Understand how disruption of nerve/muscle communication leads to neuromuscular diseases such as myasthenia, amyotrophic lateral sclerosis and aged-related muscle wasting (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.
- 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, Myology research center (France).
Arnaud Ferry, Myology research center (France).
Nathalie Sans and Mireille Montcouquiol, Magendie Neurocenter (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).
Group Leaders: Bertrand Fontaine (PU-PH, SU/APHP) and Laure Strochlic (Inserm, CR1)
Stéphanie Godard-Bauché (IE, PhD, SU)
Julien Messéant (Postdoct, AIM)
Céline Buon (IE, Inserm CDD)
Steve Cottin (IE, Inserm CDD)
Myriam Boëx (PhD student, SU)
Marius Halliez (M2 student, SU)
Olivia Cattaneo (M2 student, SU)
Gaëlle Bruneteau (PH, APHP, 20%)
Bruno Eymard (PU-PH, UPMC/APHP, 10%)
Emmanuel Fournier (PU-PH, UPMC/APHP, 10%)
Damien Sternberg (PH, APHP, 20%)
Arnaud Isapof (PH, APHP, 20%)
Savine Vicart (PH, APHP, 20%)
Karine Viala (PH, APHP, 20%)
- Boëx M, Messéant J, Bauché S, Fontaine B, Legay C. and Strochlic L. (2018). Regulation of mammalian neuromuscular junction formation and maintenance by Wnt signaling. Curr. Opin. Physiol. 04, 88–95.
- Kokunai Y, Dalle C, Vicart S, Sternberg D, Pouliot V, Bendahhou S, Fournier E, Chahine M, Fontaine B, Nicole S. (2018). A204E mutation in Na(v)1.4 DIS3 exerts gain- and loss-of-function effects that lead to periodic paralysis combining hyper- with hypo-kalaemic signs. Sci Rep. 12;8(1):16681.
- Bauché S, Vellieux G, Sternberg D, Fontenille MJ, De Bruckyeres E, Davoine CL, Brochier G, Messéant J, Wolf L, Fardeau M, Lacène E, Romero N, Koenig J, Fournier E, Hantaï D, Streichenberger N, Manel V, Lacour A, Nadaj-Paklesa A, Sukno S, Bouhour F, Laforêt P, Fontaine B, Strochlic L, Eymard B, Stojkovic T, Chevessier F and Nicole S. (2017) Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregates myopathy with synaptopathy. J. Neurol. 1791-1803.
- Messéant J, Ezan J, Delers P, Glebov K, Marchiol C, Lager F, Renault G, Tissir F, Montcouquiol M, Sans N, Legay C and Strochlic L (2017) Distinct functions of Wnt signaling regulate neuromuscular junction formation. Development, 144(9):1712-1724.
- Bauché, S., O’Regan, S., Azuma, Y., Laffargue, F., McMacken, G., Sternberg, D., Brochier, G., Buon, C., Bouzidi, N., Topf, A., Lacene, E., Remerand, G., Beaufrere, A. M., Pebrel-Richard, C., Thevenon, J., El Chehadeh-Djebbar, S., Faivre, L., Duffourd, Y., Ricci, F., Mongini, T., Fiorillo, C., Astrea, G., Burloiu, C. M., Butoianu, N., Sandu, C., Servais, L., Bonne, G., Nelson, I., Desguerre, I., Nougues, M. C., Boeuf, B., Romero, N., Laporte, J., Boland, A., Lechner, D., Deleuze, J. F., Fontaine, B., Strochlic, L., Lochmuller, H., Eymard, B., Mayer, M., & Nicole, S. (2016). Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea. American Journal of Human Genetics, 99(3), 753-761.
- Gonzalez-Bermejo J, Morélot-Panzini C, Tanguy ML, Meininger V, Pradat PF, Lenglet T, Bruneteau G, Forestier NL, Couratier P, Guy N, Desnuelle C, Prigent H, Perrin C, Attali V, Fargeot C, Nierat MC, Royer C, Ménégaux F, Salachas F, Similowski T. (2016). Early diaphragm pacing in patients with amyotrophic lateral sclerosis (RespiStimALS): a randomised controlled triple-blind trial. Lancet Neurol. 15(12), 1217-1227.
- Messéant, J., Dobbertin, A., Girard, E., Delers, P., Manuel, M., Mangione, F., Schmitt, A., Le Denmat, D., Molgo, J., Zytnicki, D., Schaeffer, L., Legay, C., & Strochlic, L. (2015). MuSK Frizzled-Like Domain Is Critical for Mammalian Neuromuscular Junction Formation and Maintenance. Journal of Neuroscience, 35(12), 4926-4941.
- Bruneteau G, Simonet T, Bauché S, Mandjee N, Malfatti E, Girard E, Tanguy ML, Behin A, Khiami F, Sariali E, Hell-Remy C, Salachas F, Pradat PF, Fournier E, Lacomblez L, Koenig J, Romero NB, Fontaine B, Meininger V, Schaeffer L, Hantaï D. (2013). Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression. Brain, 136, 2359-68.