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49 results on '"S. Bauche"'

1. Muscle Van Gogh-like 2 shapes the neuromuscular synapse by regulating MuSK signaling activity

Author: Rouche A, Dominique Langui, Mégane Lemaitre, Asha Baskaran, Boëx M, Laure Strochlic, Mireille Montcouquiol, Cottin S, Jordi Molgó, Céline Buon, S. Bauche, Nathalie Sans, Julien Messéant, Halliez M, Arnaud Ferry, Amar M, and Bertrand Fontaine
Subjects: Synapse, medicine.anatomical_structure, Kinase, Planar cell polarity, Wnt signaling pathway, medicine, Neurotransmission, Biology, Function (biology), Neuromuscular junction, Cell biology, Acetylcholine receptor
Abstract: The development of the neuromuscular junction (NMJ) requires dynamic trans-synaptic coordination orchestrated by secreted factors, including the morphogens of the Wnt family. Yet, how the signal of these synaptic cues is transduced, and particularly during the regulation of acetylcholine receptor (AChR) accumulation in the postsynaptic membrane remains unclear. We explored the function of Van Gogh-Like protein 2 (Vangl2), a core component of Wnt planar cell polarity signaling. We showed that the conditional genetic ablation of Vangl2 in muscle reproduces the NMJ differentiation defects in mice with constitutive Vangl2 deletion. These alterations persisted into adulthood with NMJs disassembly leading to an impairment of neurotransmission and motor function deficits. Mechanistically, we found that Vangl2 and the muscle-specific kinase MuSK acted in the same genetic pathway and that Vangl2 binds MuSK, thus controlling its signaling activity. Our results identify Vangl2 as a key player of the core complex of molecules shaping neuromuscular synapses and shed light on the molecular mechanisms underlying NMJ assembly.
Published: 2020
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2. Regulation of mammalian neuromuscular junction formation and maintenance by Wnt signaling

Author: Laure Strochlic, Julien Messéant, S. Bauche, Myriam Boëx, Bertrand Fontaine, and Claire Legay
Subjects: 0301 basic medicine, Synaptic cleft, Physiology, Wnt signaling network, Wnt signaling pathway, Biology, Motor function, Neuromuscular junction, Synapse, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Physiology (medical), medicine, medicine.symptom, Neuroscience, Function (biology), Confusion
Abstract: The development and maintenance of the neuromuscular connectivity relies on a temporally fine-tuned balance of distinct bi-directional communication between motor neurons and their muscle targets. Disruption of this communication leads to functional and structural defects that affect the motor function and causes severe neuromuscular pathologies. A limited number of secreted molecules exchanged across the synaptic cleft are critical for the development and maintenance of the nerve/muscle contact. Among those factors, members of the large family of Wnt molecules, best known for their role in numerous developmental processes have emerged as complex key players at the neuromuscular junction (NMJ), being possibly involved in multiple aspects of synapse positioning, differentiation and maintenance. Yet, their specific mode of action and downstream signaling in vivo remain controversial in mammals creating a certain degree of confusion as to the mechanistic frame of Wnt-elicited function at the NMJ. Recent advances in understanding the role of the Wnt signaling network during mammalian NMJ formation and maintenance is reviewed here.
Published: 2018
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3. Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy

Author: Claire-Sophie Davoine, Michel Fardeau, Damien Sternberg, Emmanuel Fournier, Marie-Joséphine Fontenille, Arnaud Lacour, Norma B. Romero, Elodie De Bruyckere, D. Hantai, Julien Messéant, Geoffroy Vellieux, Sophie Nicole, Tanya Stojkovic, Sylvie Sukno, Françoise Bouhour, Jeanine Koenig, S. Bauche, E. Lacène, Pascal Laforêt, Lucie Wolf, Laure Strochlic, Guy Brochier, Bruno Eymard, Aleksandra Nadaj-Pakleza, Frédéric Chevessier, Véronique Manel, Nathalie Streichenberger, Bertrand Fontaine, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universitätsklinikum Erlangen, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de reference des maladies neuromusculaires Nantes-Angers, CHU d'Angers et Nantes, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Roger Salengro [Lille], Centre de référence des maladies rares neuromusculaires, Centre hospitalier de Béthune, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and HAL-UPMC, Gestionnaire
Subjects: Adult, 0301 basic medicine, medicine.medical_specialty, Weakness, Glycosylation, Neurology, Adolescent, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Sarcoplasm, Neuromuscular Junction, 030105 genetics & heredity, Biology, Neuromuscular junction, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, Muscle, Skeletal, Myopathy, Aged, Retrospective Studies, Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing), Myasthenic Syndromes, Congenital, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Middle Aged, Congenital myasthenic syndrome, medicine.disease, Transmembrane protein, 3. Good health, Endocrinology, medicine.anatomical_structure, Female, Synaptopathy, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Follow-Up Studies, Myopathies, Structural, Congenital
Abstract: International audience; Mutations in GFPT1 (glutamine-fructose-6-phosphate transaminase 1), a gene encoding an enzyme involved in glycosylation of ubiquitous proteins, cause a limb-girdle congenital myasthenic syndrome (LG-CMS) with tubular aggregates (TAs) characterized predominantly by affection of the proximal skeletal muscles and presence of highly organized and remodeled sarcoplasmic tubules in patients’ muscle biopsies. We report here the first long-term clinical follow-up of 11 French individuals suffering from LG-CMS with TAs due to GFPT1 mutations, of which nine are new. Our retrospective clinical evaluation stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from three unrelated individuals demonstrates that the maintenance of neuromuscular junctions (NMJs) is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation–reinnervation processes affecting the three main NMJ components. Moreover, molecular analyses of the human muscle biopsies confirm glycosylation defects of proteins with reduced O-glycosylation and show reduced sialylation of transmembrane proteins in extra-junctional area. Altogether, these results pave the way for understanding the etiology of this rare neuromuscular disorder that may be considered as a “tubular aggregates myopathy with synaptopathy”.
Published: 2017
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4. MYASTHENIA & RELATED DISORDERS

Author: X. Latypova, Bertrand Fontaine, Fanny Laffargue, Céline Buon, S. Bauche, Julien Fauré, Alain Sureau, Arnaud Isapof, John Rendu, A. Bernabe Gelot, Damien Sternberg, Denis Furling, Bruno Eymard, Julien Messéant, M. Mayer, Marie-Christine Nougues, Myriam Boëx, and Laure Strochlic
Subjects: Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Genetics (clinical)
Published: 2020
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5. Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions

Author: Yoshiteru Azuma, Hanns Lochmüller, Sophie Nicole, Clarke R. Slater, Bruno Eymard, S. Bauche, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute of Human Genetics (NEWCASTLE UNIVERSITY), Newcastel University, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), HAL-UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, precision medicine, Neuromuscular transmission, Review, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Neuromuscular junction, 03 medical and health sciences, 0302 clinical medicine, health services administration, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], health care economics and organizations, ComputingMilieux_MISCELLANEOUS, Myasthenic Syndromes, Congenital, Heterogeneous group, neuromuscular junction, business.industry, Muscle weakness, Precision medicine, medicine.disease, Congenital myopathy, Congenital myasthenic syndromes, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Neurology, Cholinergic, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, business, Neuroscience, 030217 neurology & neurosurgery, Myasthenic syndromes
Abstract: International audience; Congenital myasthenic syndromes (CMS) form a heterogeneous group of rare diseases characterized by fatigable muscle weakness. They are genetically-inherited and caused by defective synaptic transmission at the cholinergic neuromus-cular junction (NMJ). The number of genes known to cause CMS when mutated is currently 30, and the relationship between fatigable muscle weakness and defective functions is quite well-understood for many of them. However, some of the most recent discoveries in individuals with CMS challenge our knowledge of the NMJ, where the basis of the pathology has mostly been investigated in animal models. Frontier forms between CMS and congenital myopathy, which have been genetically and clinically identified, underline the poorly understood interplay between the synaptic and extrasynaptic molecules in the neuromuscular system. In addition, precise electrophysiological and histopathological investigations of individuals with CMS suggest an important role of NMJ plasticity in the response to CMS pathogenesis. While efficient drug-based treatments are already available to improve neuromuscular transmission for most forms of CMS, others, as well as neurological and muscular comorbidities, remain resistant. Taken together, the available pathological data point to physiological issues which remain to be understood in order to achieve precision medicine with efficient therapeutics for all individuals suffering from CMS.
Published: 2017
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6. Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea

Author: Seana O'Regan, Tiziana Mongini, Céline Buon, Anne Marie Beaufrere, Yoshiteru Azuma, Bertrand Fontaine, Hanns Lochmüller, S. Bauche, Ana Töpf, Chiara Fiorillo, Jean-François Deleuze, E. Lacène, Julien Thevenon, Gisèle Bonne, Damien Sternberg, C. Burloiu, Yannis Duffourd, Isabelle Desguerre, Isabelle Nelson, Guy Brochier, Anne Boland, Benoit Bœuf, Michèle Mayer, Laure Strochlic, Jocelyn Laporte, Laurence Faivre, Sophie Nicole, Ganaelle Remerand, Céline Pebrel-Richard, Laurent Servais, Federica Ricci, Guja Astrea, Doris Lechner, Salima El Chehadeh-Djebbar, Nassima Bouzidi, Fanny Laffargue, Bruno Eymard, Marie Christine Nougues, Norma B. Romero, Grace McMacken, Carmen Sandu, Niculina Butoianu, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Newcastle University [Newcastle], Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Clermont-Ferrand, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Université Bourgogne Franche-Comté [COMUE] (UBFC), FHU TRANSLAD, Département de Génétique, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Università degli studi di Torino = University of Turin (UNITO), Università degli studi di Genova = University of Genoa (UniGe), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Service de Génétique Médical, CHU Pitié-Salpêtrière [APHP], Unité de Morphologie Neuromusculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie moléculaire et cellulaire de la différenciation, Université Joseph Fourier - Grenoble 1 (UJF)-Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Thérapie des maladies du muscle strié, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en myologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Albert Einstein College of Medicine, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatriques et maladies du dévéloppement, Service de neuropédiatrie [Trousseau], AFM-Telethon 20030Fondation Maladies Rares within the Myocapture sequencing project Medical Research Council UK G1002274 98482 European Union Seventh Framework Programme (FP7) 305444 305121, [ANR-10-IAIHU-06],« Investissements d'avenir » ,Agence nationale de la recherche (ANR), ANR-10-INBS-09-01/10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Albert Einstein College of Medicine [New York], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: 0301 basic medicine, Male, Apnea, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, receptors, respiratory rhythm, Compound heterozygosity, Synaptic Transmission, 0302 clinical medicine, Genetics(clinical), Exome, neurotransmission, Child, Genetics (clinical), Arthrogryposis, Muscle Weakness, Symporters, Homozygote, deficiency, Congenital myasthenic syndrome, Hypotonia, Cholinergic Neurons, 3. Good health, medicine.anatomical_structure, acetyltransferase, Child, Preschool, butyrylcholinesterase, Muscle Hypotonia, Female, medicine.symptom, medicine.medical_specialty, Heterozygote, Adolescent, Mutation, Missense, Neuromuscular Junction, Presynaptic Terminals, Genes, Recessive, Butyrylcholinesterase, HEK293 Cells, Humans, Infant, Infant, Newborn, Mutation, Myasthenia Gravis, Genetics, Neuromuscular junction, 03 medical and health sciences, neuromuscular-junction, Internal medicine, Report, expression, medicine, Recessive, Cholinergic neuron, Preschool, business.industry, Muscle weakness, Newborn, medicine.disease, mutations, Choline transporter, 030104 developmental biology, Endocrinology, Genes, Cholinergic, Missense, business, knockout mouse, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMS5), a clinically and genetically heterogeneous group of rare diseases with fluctuating fatigable muscle weakness as the clinical hallmark. Whole-exome sequencing and Sanger sequencing in six unrelated families identified compound heterozygous and homozygous mutations in SLC5A7 encoding the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT), which is known to be mutated in one dominant form of distal motor neuronopathy (DHMN7A). We identified 11 recessive mutations in SLC5A7 that were associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS with episodic apnea and a favorable prognosis when well managed at the clinical level. As expected given the critical role of CHT for multisystemic cholinergic neurotransmission, autonomic dysfunctions were reported in the antenatal form and cognitive impairment was noticed in half of the persons with the neonatal form. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. Increased synaptic expression of butyrylcholinesterase was also observed, exposing the dysfunction of cholinergic metabolism when CHT is deficient in vivo. This work broadens the clinical spectrum of human diseases resulting from reduced CHT activity and highlights the complexity of cholinergic metabolism at the synapse.
Published: 2016
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7. Identification of an Agrin Mutation that Causes Congenital Myasthenia and Affects Synapse Function

Author: Michel Fardeau, Laurent Schaeffer, Thierry Kuntzer, Isabelle Grosjean, Daniel Hantaï, A. Rouche, Annie Chaboud, Asma Ben Ammar, Nektaria Alexandri, Frédéric Chevessier, Caroline Huzé, Emmanuel Fournier, Andrea Brancaccio, K. Gaudon, Bruno Eymard, Jeanine Koenig, S. Bauche, Evelyne Goillot, Véronique Bernard, Heba-Aude Lecuyer, Pascale Richard, Markus A. Rüegg, Laboratoire de Biologie Moléculaire de la Cellule ( LBMC ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP)-Centre de Génétique Moléculaire et Chromosomique du GH Pitié-Salpêtrière-CHU Pitié-Salpêtrière [APHP], Max-Planck-Institut für Medizinische Forschung, Max-Planck-Gesellschaft, Institut National de Neurologie, Université Tunis El Manar ( UTM ), Plateau d'analyse des protéines, IFR128, Biologie des Jonctions Neuromusculaires Normales et Pathologiques ( U686 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Nerve-muscle unit, neurology service, Université de Lausanne ( UNIL ) -Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ), Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service d'électrophysiologie, Istituto di Chimica del Riconoscimento Molecolare, Università Cattolica del Sacro Cuore, Biozentrum, University of Basel ( Unibas ), ANR-07-MRAR-0001,MRAR,Syndromes myasthéniques congénitaux : le réseau français et approches fondamentales ( 2007 ), Hantaï, Daniel, Programme Pluriannuel de Recherche sur les Maladies Rares (MRAR) - Implication de CXCL13 et CCL21 dans les mécanismes pathogéniques de la Myasthenie. - - MG chemokines2006 - ANR-06-MRAR-0001 - MRAR - VALID, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université de Tunis El Manar (UTM), Biologie des Jonctions Neuromusculaires Normales et Pathologiques (U686), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Centre de référence des maladies rares neuromusculaires [CHU Pitié-Salpétriêre], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore [Milano] (Unicatt), Biozentrum [Basel, Suisse], University of Basel (Unibas), ANR-06-MRAR-0001,MG chemokines,Implication de CXCL13 et CCL21 dans les mécanismes pathogéniques de la Myasthenie.(2006), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)-Université de Lausanne (UNIL), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Biopsy, DNA Mutational Analysis, Muscle Fibers, Skeletal, Mutant, [SDV.GEN] Life Sciences [q-bio]/Genetics, 0302 clinical medicine, Mutant protein, CHRNE, Receptors, Cholinergic, Genetics(clinical), Dystroglycans, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Genetics, 0303 health sciences, Agrin, Congenital myasthenic syndrome, Recombinant Proteins, Pedigree, Cell biology, medicine.anatomical_structure, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Dok-7, Adult, animal structures, Mutation, Missense, Neuromuscular Junction, Biology, Article, Neuromuscular junction, Cell Line, 03 medical and health sciences, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Muscle, Skeletal, 030304 developmental biology, Acetylcholine receptor, Myasthenic Syndromes, Congenital, [SDV.GEN]Life Sciences [q-bio]/Genetics, Correction, medicine.disease, Protein Structure, Tertiary, Rats, Models, Chemical, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Synapses, 030221 ophthalmology & optometry, biology.protein, Agrin/chemistry, Agrin/genetics, Dystroglycans/metabolism, Muscle Fibers, Skeletal/cytology, Muscle Fibers, Skeletal/metabolism, Muscle, Skeletal/metabolism, Muscle, Skeletal/pathology, Myasthenic Syndromes, Congenital/genetics, Neuromuscular Junction/genetics, Neuromuscular Junction/metabolism, Receptors, Cholinergic/genetics, Receptors, Cholinergic/metabolism, Recombinant Proteins/chemistry, Recombinant Proteins/metabolism, Synapses/metabolism, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery
Abstract: International audience; We report the case of a congenital myasthenic syndrome due to a mutation in AGRN, the gene encoding agrin, an extracellular matrix molecule released by the nerve and critical for formation of the neuromuscular junction. Gene analysis identified a homozygous missense mutation, c.5125G>C, leading to the p.Gly1709Arg variant. The muscle-biopsy specimen showed a major disorganization of the neuromuscular junction, including changes in the nerve-terminal cytoskeleton and fragmentation of the synaptic gutters. Experiments performed in nonmuscle cells or in cultured C2C12 myotubes and using recombinant mini-agrin for the mutated and the wild-type forms showed that the mutated form did not impair the activation of MuSK or change the total number of induced acetylcholine receptor aggregates. A solid-phase assay using the dystrophin glycoprotein complex showed that the mutation did not affect the binding of agrin to alpha-dystroglycan. Injection of wild-type or mutated agrin into rat soleus muscle induced the formation of nonsynaptic acetylcholine receptor clusters, but the mutant protein specifically destabilized the endogenous neuromuscular junctions. Importantly, the changes observed in rat muscle injected with mutant agrin recapitulated the pre- and post-synaptic modifications observed in the patient. These results indicate that the mutation does not interfere with the ability of agrin to induce postsynaptic structures but that it dramatically perturbs the maintenance of the neuromuscular junction.
Published: 2009
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8. Formation et régénération synaptique

Author: K. Buffenoir, Michel Wager, Philippe Rigoard, F. Lapierre, Jean-Philippe Giot, S. d’Houtaud, S. Bauche, and E. Sztermer
Subjects: Nervous system, Agrin, Synaptogenesis, Biology, Neuromuscular junction, medicine.anatomical_structure, Motor Endplate, nervous system, Postsynaptic potential, Immunology, medicine, Neuregulin, Surgery, Neurology (clinical), Neuroscience, Synapse maturation
Abstract: Synapse formation is probably the key process in neural development allowing signal transmission between nerve cells. As an interesting model of synapse maturation, we considered first the neuromuscular junction (NMJ), whose development is particularly dependent on intercellular interactions between the motor nerve and the skeletal muscle. Nerve and muscle have distinct roles in synaptic compartment differentiation. The initial steps of this differentiation and motor endplate formation require several postsynaptic molecular agents including agrin, the tyrosine kinase receptor MuSK and rapsyn. The agrin or motoneuron dependence of this process continues to be debated while the following steps of axonal growth and postsynaptic apparatus maintenance essentially depend on neuronal agrin and a neuron-specific signal dispersing ectopic AChR aggregate remainders, possibly mediated by acetylcholine itself. Neuregulin is essentially involved in Schwann's cell survival and guidance for axonal growth. In this paper, we will discuss the similarities between Central Nervous System (CNS) synaptic formation and Motor innervation. The limited ability of the CNS to create new synapses after nervous system injury will be then discussed with a final consideration of some new strategies elaborated to circumvent the limitations of lesion extension processes.
Published: 2009
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9. Modalités et outils d’observation de la jonction neuromusculaire

Author: F. Seguin, K. Buffenoir, M. Fares, Daniel Hantaï, C. Huze, Jean-Philippe Giot, Laurent Schaeffer, S. Bauche, Jeanine Koenig, Philippe Rigoard, and J.-M. Maixent
Subjects: medicine.medical_specialty, medicine.anatomical_structure, medicine, Surgery, Neurology (clinical), Neurotransmission, Biology, Neuroscience, Free nerve ending, Neuromuscular junction
Abstract: A few decades ago, the neuromuscular junction (NMJ) concept was reduced to two elements: the nerve ending and the facing muscular zone. This description has since changed substantially based on recent studies conducted on the molecular aspects of neurotransmission. The aim of this paper is to provide a synthetic view of the major morphological, molecular and electrophysiological tools used in the analysis of NMJ architecture and its functional characterization.
Published: 2009
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10. Organisation structurale, moléculaire, formation et maturation de la jonction neuromusculaire

Author: S. Bauche, F. Lapierre, Jeanine Koenig, Philippe Rigoard, Jean-Philippe Giot, Michel Wager, K. Buffenoir, and Daniel Hantaï
Subjects: Agrin, Chemistry, Neuromuscular transmission, Skeletal muscle, Schwann cell, Anatomy, Neuromuscular junction, Cell biology, medicine.anatomical_structure, Motor Endplate, nervous system, Postsynaptic potential, medicine, Neuregulin, Surgery, Neurology (clinical)
Abstract: The neuromuscular junction is made up of the apposition of highly differentiated domains of three types of cell: the motor neuronal ending, the terminal Schwann cell and the muscle postsynaptic membrane. These three components are surrounded by a basal lamina, dedicated to molecular signal exchanges controlling neuromuscular formation, maturation and maintenance. This functional and structural differentiated complex conducts synaptic neurotransmission to the skeletal muscle fiber. Nerve and muscle have distinct roles in synaptic compartment differentiation. The initial steps of this differentiation and the motor endplate formation require several postsynaptic molecular agents including agrin, the tyrosine kinase receptor MuSK. Neuregulin is essentially involved in Schwann cell survival and guidance for axonal growth.
Published: 2009
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11. Existe-t-il un retentissement sur la jonction neuromusculaire de rat lors de lésions du système nerveux central ?

Author: N. Boildieu, K. Buffenoir, S. Bauche, Daniel Hantaï, Jeanine Koenig, M. Fares, F. Lapierre, M. Chaillou, F. Seguin, Da Costa L, J.-M. Maixent, and Philippe Rigoard
Subjects: Denervation, Pathology, medicine.medical_specialty, business.industry, Central nervous system, Amyotrophy, medicine.disease, Neuromuscular junction, Pathophysiology, Peripheral, law.invention, medicine.anatomical_structure, nervous system, Confocal microscopy, law, medicine, Immunohistochemistry, Surgery, Neurology (clinical), business
Abstract: STATE OF THE ART In humans, it is currently believed that peripheral nerves remain intact after central nervous system (CNS) injuries. This should lead us to observe a lack of amyotrophy in the peripheral projection areas of CNS damage. Nevertheless, the appearance of amyotrophy, described as underuse amyotrophy, is common in victims of CNS injury. Its pathophysiology remains poorly understood and is currently being debated. Amyotrophy could result directly from the structural deterioration of a nervous fiber in the muscular area corresponding to the CNS injury caused by neuromuscular junction (NMJ) changes. AIMS OF THIS STUDY The aims of this study were to assess the repercussions of a CNS injury on the NMJ and peripheral nerve complex and to evaluate the involvement of peripheral nerves and NMJs in plasticity. METHODOLOGY Peripheral nerve and muscle biopsies were collected from a group of 35 female Wistar rats that had previously undergone a thoracic spinal cord hemisection (15 rats at the T2 level (group 1), 15 rats at the T6 level (group 2), and 5 matched rats used as controls). We studied the localization and expression of the NMJ molecular components in muscle specimens by immunohistochemistry using confocal microscopy. We also searched for signs of nerve and muscle degeneration using light and electron microscopy. RESULTS We observed nonpathologic NMJs coexisting with completely denervated and partially reinnervated NMJs. We also found characteristics of embryonic behavior in rat axons secondary to axonal caliber distortions. Some authors associate this decrease in axonal activity with physiological denervation. CONCLUSION This project was designed to improve the understanding of the mechanisms involved in the interactions between the first and second motoneurons after different types of CNS injuries, with variable functional repercussions. Our results strongly suggest that CNS injuries lead to both morphological and functional repercussions at the NMJ and the peripheral nerve.
Published: 2009
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12. Le support anatomique de la contraction musculaire

Author: S. Bauche, M. Scepi, Michel Wager, F. Lapierre, Jean-Philippe Giot, Philippe Rigoard, Jean-Pierre Richer, Jean-Pierre Faure, and K. Buffenoir
Subjects: Chemistry, Skeletal muscle, Anatomy, Sarcomere, Neuromuscular junction, medicine.anatomical_structure, Myosin, medicine, Biophysics, Myocyte, Surgery, Neurology (clinical), medicine.symptom, Myofibril, Actin, Muscle contraction
Abstract: Muscle fiber action participates in a true contractile machinery associated with noncontractile components providing mechanical stability. The myofibril, the muscle fiber subentity, has an extremely consistent architecture, composed of longitudinal cylindrical units called sarcomeres, the skeletal muscle length functional unit, a highly important place in the transduction of chemical signal into mechanical contractile energy, for the most part mediated by calcium. The sarcoplasmic reticulum is the other major component of muscle fiber and is dedicated to calcium storage, liberation and distribution to the fiber, under the influence of action potential propagation. This phenomenon is called excitation-contraction coupling. This paper explores muscle anatomy from its main embryologic stages of development to its histochemical specificity, including its molecular constitution, and details the main morphofunctional relations supporting muscle contraction.
Published: 2009
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13. Caractérisation physiopathologique, moléculaire et métabolique de la jonction neuromusculaire et du nerf périphérique après lésion du système nerveux central chez l’homme

Author: K. Buffenoir, N. Boildieu, L. Da Costa, F. Lapierre, Philippe Rigoard, F. Seguin, S. Bauche, Jeanine Koenig, and J.-M. Maixent
Subjects: business.industry, Neuromuscular transmission, Anatomy, Neurotransmission, Neurotomy, Neuromuscular junction, Pathophysiology, Peripheral, Lesion, medicine.anatomical_structure, medicine, Spastic, Surgery, Neurology (clinical), medicine.symptom, business
Abstract: From the elaborate information processing that takes place in the brain to the contraction of skeletal muscles, the neurotransmission pathways involve, at least in part, (1) in tissue, Na+, K+-ATPase electrogenesis making action potential (AP) propagation possible and (2) in the cell, the synthesis, maturation, and renewal of an amazing number of molecules concentrated at the neuromuscular junction (NMJ). Our aim is to clarify CNS and peripheral nerve system (PNS) interactions by determining whether the partial motor recovery sometimes observed after a lesion of the first motoneuron is related to (1) changes in active transportation of the ions in peripheral nerve and/or muscle and (2) morphological and/or molecular changes at the NMJ, illustrating a dysfunction. Peripheral nerve surgery is proposed to some spastic patients who have recovered partially after CNS lesions to improve their gait. During these surgical procedures, the nerve and muscle samples that are usually resected can be collected and analyzed. Here, we report on eight patients who showed strictly similar motor recovery 2 years after massive CNS lesions and who underwent a selective tibial neurotomy for a spastic equinus foot. In these eight spastic patients, we performed a pathophysiological, molecular, and metabolic study of their neuromuscular junctions and peripheral nerves to characterize the dysfunction of the neuromuscular transmission after a permanent CNS injury.
Published: 2009
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14. Remaniements expérimentaux et pathologiques de la jonction neuromusculaire

Author: D. Nicolle, Daniel Hantaï, A. Ben Ammar, Jeanine Koenig, Philippe Rigoard, Bruno Eymard, and S. Bauche
Subjects: business.industry, fungi, Motor nerve, Anatomy, Motor neuron, Neuromuscular junction, chemistry.chemical_compound, medicine.anatomical_structure, nervous system, chemistry, Postsynaptic potential, medicine, Surgery, Neurology (clinical), medicine.symptom, Axon, Neurotransmitter, business, Neuroscience, Reinnervation, Muscle contraction
Abstract: The objective of our study was to investigate the cellular communication between the axon and its postsynaptic targets in the synapse. We used the neuromuscular junction (NMJ) model, which is a highly specialized structure between the nerve, the muscle, and the Schwann cell terminal where the motor neuron orders the muscle to contract. We used experimental models of motor nerve reimplantation in a denervated muscle to determine whether 1) the formation of new NMJ could participate in reinnervation of the muscle necessary to contraction or 2) the blockage of neurotransmitter release using botulinum toxin could be compensated by the formation of new NMJ. We also studied human genetic diseases that affect neuromuscular transmission--congenital myasthenic syndromes--to identify the mutations in the genes coding for synaptic molecules and to analyze the compensatory processes involved in NMJ dysfunction so that muscle contraction can occur in these conditions.
Published: 2009
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15. Organisation anatomique et physiologique du nerf périphérique

Author: Jean-Philippe Giot, S. Bauche, Philippe Rigoard, F. Lapierre, R. Robert, K. Buffenoir, and Michel Wager
Subjects: Sensory system, Anatomy, Biology, Neuromuscular junction, Peripheral, Myelin, medicine.anatomical_structure, Peripheral nerve, Peripheral nervous system, medicine, Surgery, Neurology (clinical), Information support, Axon
Abstract: The peripheral nerve provides the pathway for motor, sensory and vegetative axons belonging to the peripheral nervous system. It transmits information between these neurons and their peripheral effectors in both directions (sensory receptors, skeletal muscles and viscera). The afferences to the periphery correspond to the nerve motor content, whereas efferences from the periphery, in charge of delivering information to the central integrators, correspond to nerve-sensitive content. This information support depends on intrinsic properties of the nerve itself. Recent advances in cellular and molecular biology have provided a better understanding of nerve physiology, which are reviewed here as an indispensable basis to the study of its pathology.
Published: 2009
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16. Principaux mécanismes impliqués dans la transmission synaptique au sein de l’appareil neuromusculaire

Author: Philippe Rigoard, Michel Wager, J.-M. Maixent, K. Buffenoir, Jean-Philippe Giot, S. Rigoard, and S. Bauche
Subjects: medicine.medical_specialty, Voltage-dependent calcium channel, Chemistry, Neuromuscular transmission, Motor neuron, Neurotransmission, Neuromuscular junction, Surgery, Acetylcholine binding, medicine.anatomical_structure, Postsynaptic potential, medicine, Biophysics, Neurology (clinical), medicine.symptom, Muscle contraction
Abstract: Neuromuscular transmission results from a double signal transduction from electric impulses to chemical messengers, taking place at a highly differentiated region, the neuromuscular junction (NMJ). A nerve cell responds to a specific stimulus by modifications of its plasmic membrane properties, generating an action potential (AP). This electric signal is transmitted along the axon to the NMJ, where it induces the voltage-gated calcium channels to open. Intracellular calcium entry leads to acetylcholine release in the synaptic space at the active zones but all scientists do not consider it the major release factor. Acetylcholine binding with its receptor at the muscle membrane generates an endplate potential when the induced depolarization is greater than the sodium voltage channel opening threshold. Muscle AP causes a muscle contraction involving the three phases. This paper will successively review the electrophysiological and molecular mechanisms involved at the pre-, inter- and postsynaptic levels. The last part of the article will discuss electromechanical considerations directly affecting the mechanical properties of the muscle fiber, most particularly the factors influencing the predetermined involvement of motor units, motor neuron electrical properties determining responses to synaptic inputs and finally the impact of recruited motor neurons and their electrical impulse rates on muscle contraction strength and velocity.
Published: 2009
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17. Syndromes myasthéniques congénitaux dus à des mutations du gène de la rapsyne

Author: Pascale Richard, E. Yasaki, Jeanine Koenig, S. Bauche, A. Barois, B. Estournet, Daniel Hantaï, M. Mayer, K. Gaudon, Bruno Eymard, Emmanuel Fournier, Cassandra Prioleau, Christine Ioos, and J.P. Leroy
Subjects: Genetics, education.field_of_study, business.industry, Population, Neuromuscular transmission, Phenotype, Neurology, Mutation (genetic algorithm), Medicine, Neurology (clinical), Allele, education, business, Gene, Founder effect, Acetylcholine receptor
Abstract: Congenital myasthenic syndromes (CMS) are genetic diseases characterized by dysfunctional neuromuscular transmission and usually start during the neonatal period. Most are due to postsynaptic abnormalities, specifically to mutations in the acetylcholine receptor (AChR) genes. In 2002, the group of A Engel reported the first cases of CMS with mutations in the gene coding rapsyn, a postsynaptic molecule which stabilizes AChR aggregates at the neuromuscular junction. Since this first publication, more than 30 other cases, including six in France, have been reported. Study of these published cases allows us to distinguish three classes of phenotypes: 1) severe neonatal cases; 2) more benign cases, starting during infancy; 3) cases with facial malformations, involving Jewish patients originating from the Near-East. Comparison of the observations of other groups with our own has led us to the following conclusions: the N88K mutation is frequent (homozygous in 50% of cases); besides the N88K mutation, the second mutation varies considerably; heterozygous allelic cases (N88K + another mutation) are severe; there is probably a founder effect in the European population. There is phenotypic variability in the homozygous N88K cases, with benign cases and severe cases of early expression. A Engel and colleagues report that the seven cases of benign CMS with facial malformation, previously described in the Jewish population of Iraq and Iran, were caused by mutation in the promoter region of the rapsyn gene.
Published: 2004
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18. Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy

Author: Daniel Hantaï, Sophie Nicole, Yasmin Issop, Teresinha Evangelista, Marie-Joséphine Fontenille, Angela Abicht, Helen Griffin, Emmanuel Fournier, Damien Sternberg, Marina Dusl, A. Barois, Elodie De Bruyckere, Christine Ioos, Bruno Eymard, Amina Chaouch, Erik Stålberg, Dan Cox, Guy Brochier, S. Bauche, Hanns Lochmüller, Steven H. Laval, S. Løseth, Marijke Van Ghelue, Juliane S. Müller, T. Torbergsen, Morten Andreas Horn, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], University Hospital of North Norway [Tromsø] (UNN), Oslo University Hospital [Oslo], Uppsala University Hospital, Hôpital Raymond Poincaré [Garches], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ludwig-Maximilians University [Munich] (LMU), and godard-bauché, Stéphanie
Subjects: Adult, Male, medicine.medical_specialty, presynaptic, Molecular Sequence Data, Neuromuscular transmission, distal myopathy, Biology, Muscle disorder, Neuromuscular junction, [SHS]Humanities and Social Sciences, Internal medicine, medicine, Humans, Agrin, Amino Acid Sequence, Myopathy, Myasthenic Syndromes, Congenital, Muscle Weakness, neuromuscular junction, Muscle weakness, Congenital myasthenic syndrome, Middle Aged, medicine.disease, Pedigree, Muscular Atrophy, medicine.anatomical_structure, Endocrinology, congenital myasthenic syndrome, Distal Myopathies, Female, Neurology (clinical), [SHS] Humanities and Social Sciences, medicine.symptom, Atrophy
Abstract: International audience; Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of rare diseases resulting from impaired neuromuscular transmission. Their clinical hallmark is fatigable muscle weakness associated with a decremental muscle response to repetitive nerve stimulation and frequently related to postsynaptic defects. Distal myopathies form another clinically and genetically heterogeneous group of primary muscle disorders where weakness and atrophy are restricted to distal muscles, at least initially. In both congenital myasthenic syndromes and distal myopathies, a significant number of patients remain genetically undiagnosed. Here, we report five patients from three unrelated families with a strikingly homogenous clinical entity combining congenital myasthenia with distal muscle weakness and atrophy reminiscent of a distal myopathy. MRI and neurophysiological studies were compatible with mild myopathy restricted to distal limb muscles, but decrement (up to 72%) in response to 3 Hz repetitive nerve stimulation pointed towards a neuromuscular transmission defect. Post-exercise increment (up to 285%) was observed in the distal limb muscles in all cases suggesting presynaptic congenital myasthenic syndrome. Immunofluorescence and ultrastructural analyses of muscle end-plate regions showed synaptic remodelling with denervation-reinnervation events. We performed whole-exome sequencing in two kinships and Sanger sequencing in one isolated case and identified five new recessive mutations in the gene encoding agrin. This synaptic proteoglycan with critical function at the neuromuscular junction was previously found mutated in more typical forms of congenital myasthenic syndrome. In our patients, we found two missense mutations residing in the N-terminal agrin domain, which reduced acetylcholine receptors clustering activity of agrin in vitro. Our findings expand the spectrum of congenital myasthenic syndromes due to agrin mutations and show an unexpected correlation between the mutated gene and the associated phenotype. This provides a good rationale for examining patients with apparent distal myopathy for a neuromuscular transmission disorder and agrin mutations.
Published: 2014
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19. Peripheral nerve hyperexcitability with preterminal nerve and neuromuscular junction remodeling is a hallmark of Schwartz-Jampel syndrome

Author: Delphine Boërio, Michel Fardeau, Bertrand Fontaine, Véronique Bernard, Sophie Nicole, S. Bauche, Bruno Eymard, Jeanine Koenig, Claire-Sophie Davoine, Daniel Hantaï, Norma B. Romero, Emmanuel Fournier, Morgane Stum, Antoine Gueguen, Cécile Bureau, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CNRS, Laboratoire de Neurobiologie et Développement, Centre National de la Recherche Scientifique (CNRS), Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physico-Chimie-Curie (PCC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Receptor, ErbB-3, Schwartz–Jampel syndrome, [SDV]Life Sciences [q-bio], Neuromuscular transmission, Neural Conduction, Neuromuscular Junction, Perlecan, Biology, Osteochondrodysplasias, Neuromuscular junction, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Neurofilament Proteins, medicine, Humans, Receptors, Cholinergic, Peripheral Nerves, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Denervation, 0303 health sciences, Electromyography, Calcium-Binding Proteins, S100 Proteins, Electromyoneurography, Receptor Protein-Tyrosine Kinases, Myelin Basic Protein, Anatomy, medicine.disease, Acetylcholinesterase, medicine.anatomical_structure, Neurology, chemistry, Pediatrics, Perinatology and Child Health, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), 030217 neurology & neurosurgery, Reinnervation
Abstract: Schwartz-Jampel syndrome (SJS) is a recessive disorder with muscle hyperactivity that results from hypomorphic mutations in the perlecan gene, a basement membrane proteoglycan. Analyses done on a mouse model have suggested that SJS is a congenital form of distal peripheral nerve hyperexcitability resulting from synaptic acetylcholinesterase deficiency, nerve terminal instability with preterminal amyelination, and subtle peripheral nerve changes. We investigated one adult patient with SJS to study this statement in humans. Perlecan deficiency due to hypomorphic mutations was observed in the patient biological samples. Electroneuromyography showed normal nerve conduction, neuromuscular transmission, and compound nerve action potentials while multiple measures of peripheral nerve excitability along the nerve trunk did not detect changes. Needle electromyography detected complex repetitive discharges without any evidence for neuromuscular transmission failure. The study of muscle biopsies containing neuromuscular junctions showed well-formed post-synaptic element, synaptic acetylcholinesterase deficiency, denervation of synaptic gutters with reinnervation by terminal sprouting, and long nonmyelinated preterminal nerve segments. These data support the notion of peripheral nerve hyperexcitability in SJS, which would originate distally from synergistic actions of peripheral nerve and neuromuscular junction changes as a result of perlecan deficiency.
Published: 2013
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20. Correction: A Mutation Causes MuSK Reduced Sensitivity to Agrin and Congenital Myasthenia

Author: Osamu Higuchi, Pascale Richard, Jeanine Koenig, Asma Ben Ammar, Daniel Hantaï, K. Gaudon, Hossein Najmabadi, Kimia Kahrizi, Antoine Taly, Manouchehr Ilkhani, Yuji Yamanashi, Evelyne Goillot, Caroline Huzé, Bruno Eymard, Michel Fardeau, Ruth Herbst, Fayçal Hentati, Payam Soltanzadeh, S. Bauche, Jean-Paul Leroy, and Laurent Schaeffer
Subjects: 0303 health sciences, Multidisciplinary, Agrin, business.industry, Science, lcsh:R, Correction, lcsh:Medicine, Congenital myasthenia, 03 medical and health sciences, 0302 clinical medicine, Mutation (genetic algorithm), Medicine, lcsh:Q, Theology, business, lcsh:Science, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The following information was missing from the funding section: Austrian Science Fund ({"type":"entrez-protein","attrs":{"text":"P21667","term_id":"122622","term_text":"P21667"}}P21667-B09).
Published: 2013

21. A Mutation Causes MuSK Reduced Sensitivity to Agrin and Congenital Myasthenia

Author: Jeanine Koenig, Osamu Higuchi, Antoine Taly, Laurent Schaeffer, K. Gaudon, Asma Ben Ammar, Yuji Yamanashi, Pascale Richard, Kimia Kahrizi, Jean-Paul Leroy, Hossein Najmabadi, Daniel Hantaï, Evelyne Goillot, Fayçal Hentati, Bruno Eymard, Ruth Herbst, Caroline Huzé, Michel Fardeau, Payam Soltanzadeh, S. Bauche, Manouchehr Ilkhani, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Neurobiologie Moléculaire et Neuropathologie, Université de Tunis El Manar (UTM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Center for Brain Research, Medizinische Universität Wien = Medical University of Vienna, The University of Tokyo (UTokyo), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Genetics Research Center, University of Social Welfare and Rehabilitation Sciences [Tehran], Department of Neurology, Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University-Shahid Beheshti University, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance Publique-Hopitaux de Paris [PHRC AOM 1036], Reseaux Inserm, ANR-Maladies Rares [ANR-07-MRAR-001], Association Francaise contre les Myopathies (AFM), Comite Mixte Franco-Tunisien pour la Cooperation Universitaire (CMCU Project) [05G0809], AFM, Contrat hospitalier de recherche translationnelle AP-HP Inserm, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Department of Cancer Biology, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Brain Research [Vienna, Austria], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), HAL UPMC, Gestionnaire, École Pratique des Hautes Études (EPHE), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Anatomy and Physiology, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neuromuscular transmission, Muscle Proteins, lcsh:Medicine, Synaptic Transmission, Biochemistry, Mice, 0302 clinical medicine, Neurobiology of Disease and Regeneration, Missense mutation, Receptors, Cholinergic, Child, lcsh:Science, Denervation, 0303 health sciences, Multidisciplinary, Agrin, Muscle Weakness, Neurochemistry, Neuromuscular Diseases, medicine.anatomical_structure, Neurology, Medicine, medicine.symptom, Neurochemicals, Reinnervation, Signal Transduction, Research Article, medicine.medical_specialty, animal structures, Mutation, Missense, Neuromuscular Junction, Neurophysiology, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Neuromuscular junction, Neurological System, 03 medical and health sciences, Genetic Mutation, Internal medicine, medicine, Genetics, Animals, Humans, Receptors, Growth Factor, Muscle, Skeletal, 030304 developmental biology, Acetylcholine receptor, Myasthenic Syndromes, Congenital, Motor Systems, lcsh:R, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Muscle weakness, Receptor Protein-Tyrosine Kinases, Proteins, Acetylcholine, Endocrinology, HEK293 Cells, nervous system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Acetylcholine Receptors, Cellular Neuroscience, lcsh:Q, 030217 neurology & neurosurgery, Neuroscience
Abstract: International audience; Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A.G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre-and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient's biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin-and Dok-7-dependent phosphorylation.
Published: 2013
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22. Multiexon deletions account for 15% of Congenital Myasthenic Syndrome with RAPSN mutations after negative DNA Sequencing

Author: Asma Ben Ammar, L. Demay, Isabelle Pénisson-Besnier, Guillaume Nicolas, Françoise Bouhour, Daniel Hantaï, Bruno Eymard, S. Bauche, K. Gaudon, Brigitte Chabrol, Christophe Vial, Pascale Richard, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital neurologique, Hospices Civils de Lyon (HCL), INN, Université de Tunis El Manar (UTM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence des maladies rares neuromusculaires, Centre Hospitalier Universitaire d'Angers (CHU Angers), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Histoire naturelle de l'Homme préhistorique (HNHP), Muséum national d'Histoire naturelle (MNHN)-Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), Department of Gastroenterology, Hôpital La Rabta [Tunis], Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire de Recherches Juridique et Economique (LARJE), Université de la Nouvelle-Calédonie (UNC), Biogéochimie et écologie des milieux continentaux (Bioemco), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Recherche pour le Développement (IRD)-Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-AgroParisTech-Centre National de la Recherche Scientifique (CNRS), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Peer, Hal, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Adult, medicine.medical_specialty, Adolescent, Genetic counseling, [SDV]Life Sciences [q-bio], Neuromuscular transmission, Muscle Proteins, Biology, medicine.disease_cause, DNA sequencing, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Molecular genetics, Genetics, medicine, Humans, Allele, Child, Gene, Genetics (clinical), Sequence Deletion, Myasthenic Syndromes, Congenital, 0303 health sciences, Mutation, 030305 genetics & heredity, Infant, Newborn, Neurosciences, Infant, Exons, Sequence Analysis, DNA, Neuromuscular disease, 3. Good health, RAPSN, Neurology, Female, 030217 neurology & neurosurgery
Abstract: International audience; Introduction: Post-synaptic congenital myasthenic syndromes (CMSs) (OMIM_ #608931) is a group of genetic disorders affecting neuromuscular transmission and due to acetylcholine receptor (AChR) deficiency in 80% of cases.[1] These autosomal recessive CMSs may be caused by mutations in genes encoding the AChR or one of the AChR-clustering or anchoring proteins, rapsyn, Dok-7 or MuSK.[1-4] Spectra of rapsyn mutations show allelic heterogeneity and suggest that the common substitution p.Asn88Lys (N88K) (variant_021217 in Q13702) results in less stable AChR clusters.[5] Until recently, all patients harbouring mutations in RAPSN are either homozygous for the p.Asn88Lys substitution or heteroallelic for p.Asn88Lys and a mutation which is in most of cases an amino acid substitution but can be also a null allele.[6] Analysis of disease severity in patients suggested that the second mutant allele may largely determine severity of the phenotype.[7] Recently, a patient with two non p.Asn88Lys in RAPSN has been described and the first chromosomal deletion event was described by Müller and colleagues.[8,9]
Published: 2010
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23. Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7

Author: Emmanuel Fournier, Damien Sternberg, Michel Fardeau, T. Stojkovic, François Petit, N. Pellegrini, G Stoltenburg, A. Rouche, Fayçal Hentati, N. Alexandri, Louis Viollet, D. Hantai, S. Bauche, Xavier Ferrer, K. Gaudon, Arnaud Lacour, M. Paturneau-Jouas, Bruno Eymard, Jeanine Koenig, David Orlikowski, D. Gras, L. Lazaro, Philippe Petiot, A. Ben Ammar, F. Zagnoli, Pascale Richard, Department of Gastroenterology, Hôpital La Rabta [Tunis], Service de génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences de Brest (LNB), Université de Brest (UBO), Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Réanimation Adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Child and Adolescent Psychiatry and Psychology Department, Neurosciences Institute, Hospital Clinic Barcelona, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Health Sciences Division, Psychiatry and Clinical Psychobiology Department, and University of Barcelona
Subjects: Male, Pathology, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], Neuromuscular Junction, Synaptogenesis, Neuromuscular transmission, Muscle Proteins, Biology, medicine.disease_cause, Neuromuscular junction, Cohort Studies, Pregnancy, Postsynaptic potential, medicine, Humans, Child, Muscle, Skeletal, Genetic Association Studies, Myasthenic Syndromes, Congenital, Mutation, Muscle biopsy, medicine.diagnostic_test, Infant, Newborn, Infant, Congenital myasthenic syndrome, medicine.disease, Phenotype, Axons, medicine.anatomical_structure, Neurology, Child, Preschool, Female, Neurology (clinical), Tomography, X-Ray Computed
Abstract: Congenital myasthenic syndromes (CMSs) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. Mutations of DOK7 have recently been described in recessive forms of CMS. Dok-7 is a cytoplasmic post-synaptic protein co-activator of the muscle-specific receptor-tyrosine kinase (MuSK) involved in neuromuscular synaptogenesis and maintenance. We report clinical, morphological and molecular data on 15 patients with mutations in DOK7. Eleven different mutations (5 novel) were identified and all patients but one were found to carry at least the common c.1124_1127dupTGCC mutation. Patients with DOK7 mutations have a particular limb-girdle pattern, without tubular aggregates but a frequent lipidosis on the muscle biopsy. Changes in pre- and post-synaptic compartments of the neuromuscular junction were also observed in muscle biopsies: terminal axons showed defective branching which resulted in a unique terminal axon contacting en passant postsynaptic cups. Clinical features, muscle biopsy findings or response to therapy were confusing in several patients. Characterization of this distinct phenotype is essential to provide clues for targeted genetic screening and to predict the therapeutic response to anticholinesterase treatments or ephedrine as has been suggested.
Published: 2010
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24. Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

Author: Laetitia Mazelin, Jean-François Tanti, Alban Vignaud, Klaas Romanino, Xavier Bigard, Matthias Mueller, Daniel Hantaï, Yann-Gaël Gangloff, Damien Freyssenet, Agnès Conjard-Duplany, George Thomas, Hervé Sanchez, S. Bauche, Laurent Schaeffer, Hélène Richard-Bulteau, Aurelia Defour, Sara C. Kozma, Yannick Le-Marchand-Brustel, Nathalie Koulmann, Bernard Ferrier, Arnaud Ferry, Claudine Corneloup, Dominique Baas, Mila Roceri, Valérie Risson, Mario Pende, Vincent Moncollin, Markus A. Rüegg, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Apoptose Cancer et Développement, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Département des Facteurs Humains, Service de Santé des Armées-Ministère de la Défense, Aptanomics, Centre de Recherches du Service de Santé des Armées (CRSSA), Service de Santé des Armées, Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), C3M U1065, Centre National de la Recherche Scientifique (CNRS), Biozentrum [Basel, Suisse], University of Basel (Unibas), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-06-BLAN-0354,Croissance,The coordination of muscle growth and metabolism: search for novel mTOR functions(2006), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Biozentrum, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), ANR-06,Croissance, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Carrier proteins, Utrophin, [SDV]Life Sciences [q-bio], mTORC1, mTORC2, Severity of Illness Index, Dystrophin, Mice, 0302 clinical medicine, Transduction, Genetic, Immunology and Allergy, Glucose homeostasis, Cells, Cultured, Research Articles, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, 0303 health sciences, biology, TOR Serine-Threonine Kinases, digestive, oral, and skin physiology, Age Factors, 3. Good health, Cell biology, Phosphotransferases (Alcohol Group Acceptor), Electroporation, Biochemistry, Female, biological phenomena, cell phenomena, and immunity, Oxidation-Reduction, Glycogen, medicine.drug, Muscle Contraction, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Proteïnes portadores, Immunology, Article, 03 medical and health sciences, Muscular Diseases, medicine, Animals, Muscle, Skeletal, PI3K/AKT/mTOR pathway, Malalties musculars, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Sirolimus, RPTOR, Cell Biology, Regulatory-Associated Protein of mTOR, Muscular Dystrophy, Animal, Mitochondria, Muscle, Rats, Enzyme Activation, Mice, Inbred C57BL, Glucose, Rapamycin-Insensitive Companion of mTOR Protein, Glucosa, Mutation, biology.protein, Carrier Proteins, Energy Metabolism, Proto-Oncogene Proteins c-akt, 030217 neurology & neurosurgery
Abstract: mTor, acting mainly via mTORC1, controls dystrophin transcription in a raptor- and rictor-independent mechanism., Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent.
Published: 2009
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25. Architecture moléculaire du réticulum sarcoplasmique et son rôle dans le couplage excitation-contraction

Author: K. Buffenoir, Michel Wager, Jean-Philippe Giot, Philippe Rigoard, F. Lapierre, S. Bauche, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Centre Hospitalier Universitaire [Grenoble] (CHU)
Subjects: Calcium metabolism, medicine.medical_specialty, Ryanodine receptor, Endoplasmic reticulum, Dihydropyridine, chemistry.chemical_element, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Calcium, Calcium in biology, Neuromuscular junction, Endocrinology, medicine.anatomical_structure, chemistry, Internal medicine, medicine, Biophysics, Surgery, Neurology (clinical), medicine.symptom, medicine.drug, Muscle contraction
Abstract: The sarcoplasmic reticulum (SR) plays a fundamental role in excitation-contraction coupling, which propagates the electric signal conversion along the muscle fiber's plasmic membrane to a mechanical event manifested as a muscle contraction. It plays a crucial role in calcium homeostasis and intracellular calcium storage control (storage, liberation and uptake) necessary for fiber muscle contraction and then relaxation. These functions take place at the triad, made up of individualized SR subdomains where the protein-specific organization provides efficient and fast coupling. Ryanodine receptors (RyR) and dihydropyridine receptors (DHPR) mainly act in calcium exchanges in the SR. This particular structural and molecular architecture must be correlated to its functional specificity.
Published: 2009
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26. [Morphological study of CNS lesions and the consequences on rat neuromuscular junction and peripheral nerve using confocal laser scanning microscopy and Koelle's technique]

Author: P, Rigoard, K, Buffenoir, M, Chaillou, M, Fares, L, Da Costa, N, Boildieu, F, Seguin, F, Lapierre, J-M, Maixent, S, Bauche, J, Koenig, and D, Hantaï
Subjects: Central Nervous System, Microscopy, Confocal, Neuronal Plasticity, Neuromuscular Junction, Animals, Excitatory Postsynaptic Potentials, Female, Peripheral Nerves, Rats, Wistar, Muscle, Skeletal, Spinal Cord Injuries, Rats
Abstract: In humans, it is currently believed that peripheral nerves remain intact after central nervous system (CNS) injuries. This should lead us to observe a lack of amyotrophy in the peripheral projection areas of CNS damage. Nevertheless, the appearance of amyotrophy, described as underuse amyotrophy, is common in victims of CNS injury. Its pathophysiology remains poorly understood and is currently being debated. Amyotrophy could result directly from the structural deterioration of a nervous fiber in the muscular area corresponding to the CNS injury caused by neuromuscular junction (NMJ) changes.The aims of this study were to assess the repercussions of a CNS injury on the NMJ and peripheral nerve complex and to evaluate the involvement of peripheral nerves and NMJs in plasticity.Peripheral nerve and muscle biopsies were collected from a group of 35 female Wistar rats that had previously undergone a thoracic spinal cord hemisection (15 rats at the T2 level (group 1), 15 rats at the T6 level (group 2), and 5 matched rats used as controls). We studied the localization and expression of the NMJ molecular components in muscle specimens by immunohistochemistry using confocal microscopy. We also searched for signs of nerve and muscle degeneration using light and electron microscopy.We observed nonpathologic NMJs coexisting with completely denervated and partially reinnervated NMJs. We also found characteristics of embryonic behavior in rat axons secondary to axonal caliber distortions. Some authors associate this decrease in axonal activity with physiological denervation.This project was designed to improve the understanding of the mechanisms involved in the interactions between the first and second motoneurons after different types of CNS injuries, with variable functional repercussions. Our results strongly suggest that CNS injuries lead to both morphological and functional repercussions at the NMJ and the peripheral nerve.
Published: 2008

27. [Pathophysiological, molecular and metabolic changes at the neuromuscular junction and the peripheral nerve after central nervous system lesions in humans]

Author: P, Rigoard, S, Bauche, K, Buffenoir, L, Da Costa, N, Boildieu, F, Seguin, J, Koenig, F, Lapierre, and J-M, Maixent
Subjects: Adult, Male, Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, Neuromuscular Junction, Action Potentials, Biological Transport, Active, Peripheral Nervous System Diseases, Middle Aged, Immunohistochemistry, Synaptic Transmission, Electrophysiology, Central Nervous System Diseases, Muscle Spasticity, Humans, Female, Receptors, Cholinergic, Peripheral Nerves, Schwann Cells, Sodium-Potassium-Exchanging ATPase, Aged
Abstract: From the elaborate information processing that takes place in the brain to the contraction of skeletal muscles, the neurotransmission pathways involve, at least in part, (1) in tissue, Na+, K+-ATPase electrogenesis making action potential (AP) propagation possible and (2) in the cell, the synthesis, maturation, and renewal of an amazing number of molecules concentrated at the neuromuscular junction (NMJ). Our aim is to clarify CNS and peripheral nerve system (PNS) interactions by determining whether the partial motor recovery sometimes observed after a lesion of the first motoneuron is related to (1) changes in active transportation of the ions in peripheral nerve and/or muscle and (2) morphological and/or molecular changes at the NMJ, illustrating a dysfunction. Peripheral nerve surgery is proposed to some spastic patients who have recovered partially after CNS lesions to improve their gait. During these surgical procedures, the nerve and muscle samples that are usually resected can be collected and analyzed. Here, we report on eight patients who showed strictly similar motor recovery 2 years after massive CNS lesions and who underwent a selective tibial neurotomy for a spastic equinus foot. In these eight spastic patients, we performed a pathophysiological, molecular, and metabolic study of their neuromuscular junctions and peripheral nerves to characterize the dysfunction of the neuromuscular transmission after a permanent CNS injury.
Published: 2008

28. [The anatomical substrate of muscle contractility]

Author: P, Rigoard, S, Bauche, K, Buffenoir, J-P, Giot, J-P, Faure, M, Scepi, J-P, Richer, F, Lapierre, and M, Wager
Subjects: Myofibrils, Muscle Relaxation, Action Potentials, Animals, Humans, Muscle, Skeletal, Muscle Contraction
Abstract: Muscle fiber action participates in a true contractile machinery associated with noncontractile components providing mechanical stability. The myofibril, the muscle fiber subentity, has an extremely consistent architecture, composed of longitudinal cylindrical units called sarcomeres, the skeletal muscle length functional unit, a highly important place in the transduction of chemical signal into mechanical contractile energy, for the most part mediated by calcium. The sarcoplasmic reticulum is the other major component of muscle fiber and is dedicated to calcium storage, liberation and distribution to the fiber, under the influence of action potential propagation. This phenomenon is called excitation-contraction coupling. This paper explores muscle anatomy from its main embryologic stages of development to its histochemical specificity, including its molecular constitution, and details the main morphofunctional relations supporting muscle contraction.
Published: 2008

29. [Molecular architecture of the sarcoplasmic reticulum and its role in the ECC]

Author: P, Rigoard, K, Buffenoir, M, Wager, S, Bauche, J-P, Giot, and F, Lapierre
Subjects: Electrophysiology, Sarcoplasmic Reticulum, Calcium Channels, L-Type, Animals, Humans, Ryanodine Receptor Calcium Release Channel, Muscle, Skeletal, Muscle Contraction
Abstract: The sarcoplasmic reticulum (SR) plays a fundamental role in excitation-contraction coupling, which propagates the electric signal conversion along the muscle fiber's plasmic membrane to a mechanical event manifested as a muscle contraction. It plays a crucial role in calcium homeostasis and intracellular calcium storage control (storage, liberation and uptake) necessary for fiber muscle contraction and then relaxation. These functions take place at the triad, made up of individualized SR subdomains where the protein-specific organization provides efficient and fast coupling. Ryanodine receptors (RyR) and dihydropyridine receptors (DHPR) mainly act in calcium exchanges in the SR. This particular structural and molecular architecture must be correlated to its functional specificity.
Published: 2008

30. [Synapse formation and regeneration]

Author: S, d'Houtaud, E, Sztermer, K, Buffenoir, J-P, Giot, M, Wager, S, Bauche, F, Lapierre, and P, Rigoard
Subjects: Motor Neurons, Neurotransmitter Agents, Synapses, Animals, Excitatory Postsynaptic Potentials, Humans, Cell Differentiation, Synaptic Transmission, Nerve Regeneration
Abstract: Synapse formation is probably the key process in neural development allowing signal transmission between nerve cells. As an interesting model of synapse maturation, we considered first the neuromuscular junction (NMJ), whose development is particularly dependent on intercellular interactions between the motor nerve and the skeletal muscle. Nerve and muscle have distinct roles in synaptic compartment differentiation. The initial steps of this differentiation and motor endplate formation require several postsynaptic molecular agents including agrin, the tyrosine kinase receptor MuSK and rapsyn. The agrin or motoneuron dependence of this process continues to be debated while the following steps of axonal growth and postsynaptic apparatus maintenance essentially depend on neuronal agrin and a neuron-specific signal dispersing ectopic AChR aggregate remainders, possibly mediated by acetylcholine itself. Neuregulin is essentially involved in Schwann's cell survival and guidance for axonal growth. In this paper, we will discuss the similarities between Central Nervous System (CNS) synaptic formation and Motor innervation. The limited ability of the CNS to create new synapses after nervous system injury will be then discussed with a final consideration of some new strategies elaborated to circumvent the limitations of lesion extension processes.
Published: 2008

31. [Major mechanisms involved in the synaptic transmission of the neuromuscular apparatus]

Author: S, Rigoard, M, Wager, K, Buffenoir, S, Bauche, J-P, Giot, J-M, Maixent, and P, Rigoard
Subjects: Electrophysiology, Neurotransmitter Agents, Neuromuscular Junction, Action Potentials, Animals, Excitatory Postsynaptic Potentials, Humans, Energy Metabolism, Synaptic Transmission
Abstract: Neuromuscular transmission results from a double signal transduction from electric impulses to chemical messengers, taking place at a highly differentiated region, the neuromuscular junction (NMJ). A nerve cell responds to a specific stimulus by modifications of its plasmic membrane properties, generating an action potential (AP). This electric signal is transmitted along the axon to the NMJ, where it induces the voltage-gated calcium channels to open. Intracellular calcium entry leads to acetylcholine release in the synaptic space at the active zones but all scientists do not consider it the major release factor. Acetylcholine binding with its receptor at the muscle membrane generates an endplate potential when the induced depolarization is greater than the sodium voltage channel opening threshold. Muscle AP causes a muscle contraction involving the three phases. This paper will successively review the electrophysiological and molecular mechanisms involved at the pre-, inter- and postsynaptic levels. The last part of the article will discuss electromechanical considerations directly affecting the mechanical properties of the muscle fiber, most particularly the factors influencing the predetermined involvement of motor units, motor neuron electrical properties determining responses to synaptic inputs and finally the impact of recruited motor neurons and their electrical impulse rates on muscle contraction strength and velocity.
Published: 2008

32. [Tools and techniques dedicated to neuromuscular junction observation]

Author: P, Rigoard, K, Buffenoir, S, Bauche, M, Fares, J, Koenig, D, Hantaï, J-P, Giot, F, Seguin, C, Huze, L, Schaeffer, and J-M, Maixent
Subjects: Electrophysiology, Neuromuscular Junction, Animals, Humans, Muscle, Skeletal, Synaptic Transmission
Abstract: A few decades ago, the neuromuscular junction (NMJ) concept was reduced to two elements: the nerve ending and the facing muscular zone. This description has since changed substantially based on recent studies conducted on the molecular aspects of neurotransmission. The aim of this paper is to provide a synthetic view of the major morphological, molecular and electrophysiological tools used in the analysis of NMJ architecture and its functional characterization.
Published: 2008

33. [Anatomy and physiology of the peripheral nerve]

Author: P, Rigoard, K, Buffenoir, M, Wager, S, Bauche, J-P, Giot, R, Robert, and F, Lapierre
Subjects: Regional Blood Flow, Peripheral Nervous System, Animals, Humans, Peripheral Nerves, Schwann Cells, Nerve Fibers, Myelinated, Axons
Abstract: The peripheral nerve provides the pathway for motor, sensory and vegetative axons belonging to the peripheral nervous system. It transmits information between these neurons and their peripheral effectors in both directions (sensory receptors, skeletal muscles and viscera). The afferences to the periphery correspond to the nerve motor content, whereas efferences from the periphery, in charge of delivering information to the central integrators, correspond to nerve-sensitive content. This information support depends on intrinsic properties of the nerve itself. Recent advances in cellular and molecular biology have provided a better understanding of nerve physiology, which are reviewed here as an indispensable basis to the study of its pathology.
Published: 2008

34. [Structural and molecular organization, development and maturation of the neuromuscular junction]

Author: P, Rigoard, K, Buffenoir, S, Bauche, J-P, Giot, J, Koenig, D, Hantaï, F, Lapierre, and M, Wager
Subjects: Motor Neurons, Neuromuscular Junction, Animals, Humans, Schwann Cells, Muscle, Skeletal, Motor Endplate
Abstract: The neuromuscular junction is made up of the apposition of highly differentiated domains of three types of cell: the motor neuronal ending, the terminal Schwann cell and the muscle postsynaptic membrane. These three components are surrounded by a basal lamina, dedicated to molecular signal exchanges controlling neuromuscular formation, maturation and maintenance. This functional and structural differentiated complex conducts synaptic neurotransmission to the skeletal muscle fiber. Nerve and muscle have distinct roles in synaptic compartment differentiation. The initial steps of this differentiation and the motor endplate formation require several postsynaptic molecular agents including agrin, the tyrosine kinase receptor MuSK. Neuregulin is essentially involved in Schwann cell survival and guidance for axonal growth.
Published: 2008

35. MUSK, a new target for mutations causing congenital myasthenic syndrome

Author: Evelyne Goillot, Daniel Hantaï, Aymeric Ravel-Chapuis, Michel Fardeau, Frédéric Chevessier, Ruth Herbst, Pascale Richard, Brice Faraut, Jean-Philippe Azulay, Jean Pouget, Jeanine Koenig, Bruno Eymard, Christine Ioos, S. Bauche, Shahram Attarian, Claire Legay, Emmanuel Fournier, Jean-Paul Leroy, Cassandra Prioleau, K. Gaudon, Laurent Schaeffer, Unité mixte de recherche biologie moléculaire de la cellule, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon), ProdInra, Migration, École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Coeur, Muscle et Vaisseaux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), IFR128, Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Center for Brain Research [Vienna, Austria], Medizinische Universität Wien = Medical University of Vienna, Hôpital de la Timone [CHU - APHM] (TIMONE), Sciences du cerveau et de la cognition (SCC), Université de la Méditerranée - Aix-Marseille 2-Université de Provence - Aix-Marseille 1-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Morvan - CHRU de Brest (CHU - BREST ), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neurobiologie (UMR 8544) (NEURO), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2, godard-bauché, Stéphanie, and École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Neuromuscular transmission, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [INFO] Computer Science [cs], Neuromuscular junction, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Genetics, medicine, Humans, Missense mutation, Receptors, Cholinergic, [INFO]Computer Science [cs], Kinase activity, Molecular Biology, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, EXPRESSION GENETIQUE, 030304 developmental biology, Myasthenic Syndromes, Congenital, 0303 health sciences, Polymorphism, Genetic, Agrin, biology, Muscles, Receptor Protein-Tyrosine Kinases, General Medicine, Congenital myasthenic syndrome, GENETIQUE, BIOLOGIE MOLECULAIRE, medicine.disease, Immunohistochemistry, Molecular biology, Pedigree, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Endocrinology, Mutation, biology.protein, Female, 030217 neurology & neurosurgery, Dok-7
Abstract: International audience; We report the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.
Published: 2004
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36. Possible founder effect of rapsyn N88K mutation and identification of novel rapsyn mutations in congenital myasthenic syndromes

Author: S. Bauche, F. Andreux, Daniel Hantaï, A. Barois, M C Routon, Bernard Hainque, Michel Fardeau, E. Yasaki, Emmanuel Fournier, M Mokhtari, J.P. Leroy, Bruno Eymard, P. Richard, M. Mayer, Christine Ioos, Jeanine Koenig, Cassandra Prioleau, K. Gaudon, Laboratoire de Biogéochimie Isotopique, and Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Adult, Male, Protein subunit, Neuromuscular transmission, Muscle Proteins, Biology, Receptors, Nicotinic, medicine.disease_cause, [SHS]Humanities and Social Sciences, Postsynaptic potential, Genetics, medicine, Humans, Child, Genetics (clinical), Acetylcholine receptor, Myasthenic Syndromes, Congenital, Mutation, Agrin, Lysine, Infant, Founder Effect, Pedigree, RAPSN, Tetratricopeptide, Amino Acid Substitution, Child, Preschool, Female, Online Mutation Report, Asparagine
Abstract: Congenital myasthenic syndromes (CMS) constitute a group of rare diseases heterogeneous both in terms of their mode of hereditary transmission (recessive and dominant forms) and their pathophysiology (with presynaptic, synaptic, and postsynaptic defects). They are responsible for dysfunction of neuromuscular transmission giving rise to a condition of muscle weakness which is accentuated by exertion. In most cases, CMS begin in early childhood but later onset in adulthood is possible. Severity also varies from severe with respiratory failure to mild expression.1,2 The majority of CMS primarily affect postsynaptic function and are the result of mutations located in the muscle acetylcholine receptor (AChR) subunit genes that lead to kinetic abnormalities or to AChR deficiency. For example, an increased response occurs in the slow channel syndromes associated with dominant mutations in AChR subunits delaying channel closure or increasing the affinity of the receptor for acetylcholine. However, the most commonly encountered CMS is a deficiency in AChR which occurs with recessive mutations. Most of these mutations are located in the AChR e subunit.3,4 Recent advances have shown that mutations in rapsyn are also involved in recessive forms of postsynaptic CMS and cause AChR deficiency.5 Rapsyn is a 43 kDa postsynaptic protein involved in development and maintenance of the molecular architecture of the postsynaptic membrane by participating in the clustering of AChR after binding of neural agrin to its muscle specific receptor tyrosine kinase, MuSK.6,7 The rapsyn gene ( RAPSN ) has been mapped to chromosome 11p11.2 p11.1 and comprises eight exons.8 The primary structure of rapsyn is predicted to contain several functional domains such as an N-terminus myristoylation signal, seven tetratricopeptide repeats (residues 6-279), a coiled-coiled domain (298-331), a cysteine rich RING-H2 domain (363-402), and a serine phosphorylation site at codon 406.9,10 The aim of this …
Published: 2003
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37. Corrigendum to ‘Peripheral nerve hyperexcitability with preterminal nerve and neuromuscular junction remodeling is a hallmark of Schwartz-Jampel syndrome’ [Neuromuscul Disord 23 (2013) 998–1009]

Author: Delphine Boërio, Sophie Nicole, Bruno Eymard, Michel Fardeau, Bertrand Fontaine, Daniel Hantaï, Véronique Bernard, Claire-Sophie Davoine, Morgane Stum, Jeanine Koenig, Antoine Gueguen, Cécile Bureau, Emmanuel Fournier, Norma B. Romero, and S. Bauche
Subjects: medicine.anatomical_structure, Neurology, Peripheral nerve, business.industry, Schwartz–Jampel syndrome, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), Anatomy, medicine.disease, business, Genetics (clinical), Neuromuscular junction
Published: 2014
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38. Mutations in MUSK cause congenital myasthenic syndrome

Author: Daniel Hantaï, Bruno Eymard, Frédéric Chevessier, Brice Faraut, Aymeric Ravel-Chapuis, Jean-Philippe Azulay, Michel Fardeau, S. Bauche, Karen Gaudon, Claire Legay, Jeanine Koenig, Jean-Paul Leroy, Laurent Schaeffer, Cassandra Prioleau, Emmanuel Fournier, Christine Ioos, Shahram Attarian, Pascale Richard, Ruth Herbst, Jean Pouget, and Evelyne Goillot
Subjects: Pediatrics, medicine.medical_specialty, business.industry, Physiology (medical), General Neuroscience, Medicine, Congenital myasthenic syndrome, business, medicine.disease
Published: 2006
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39. G.P.11.10 Partial genomic deletions of RAPSN account for 15% of congenital myasthenic syndrome after negative DNA sequencing

Author: P. Richard, Brigitte Chabrol, Christophe Vial, A. Ben Ammar, S. Bauche, Bruno Eymard, Isabelle Pénisson-Besnier, Daniel Hantaï, Françoise Bouhour, and K. Gaudon
Subjects: Genetics, RAPSN, Neurology, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), Congenital myasthenic syndrome, Biology, medicine.disease, Molecular biology, Genetics (clinical), DNA sequencing
Published: 2009
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40. Long-term follow-up of patients with congenital myasthenic syndrome caused by COLQ mutations.

Author: Wargon I, Richard P, Kuntzer T, Sternberg D, Nafissi S, Gaudon K, Lebail A, Bauche S, Hantaï D, Fournier E, Eymard B, and Stojkovic T
Subjects: Acetylcholinesterase deficiency, Acetylcholinesterase metabolism, Adolescent, Adult, Child, Child, Preschool, Collagen metabolism, Disease Progression, Female, Follow-Up Studies, Genetic Association Studies, Humans, Male, Middle Aged, Muscle Proteins metabolism, Phenotype, Recurrence, Treatment Outcome, Young Adult, Acetylcholinesterase genetics, Collagen genetics, Muscle Proteins genetics, Mutation genetics, Myasthenic Syndromes, Congenital diagnosis, Myasthenic Syndromes, Congenital genetics
Abstract: Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COlQ) cause recessive forms of synaptic CMS with end plate AChE deficiency. We present data on 15 COLQ -mutant CMS carrying 16 different mutations (9 novel ones identified) followed-up for an average period of 10 ears. The mean age at the first examination was 19 ears old (range from 3 to 48). We report relapses during short or long-term periods characterized by worsening of muscle weakness sometimes associated with respiratory crises. All the relapses ended spontaneously or with 3-4 DAP or ephedrine with no residual impairment. The triggering factors identified were esterase inhibitors, effort, puberty or pregnancy highlighting the importance of hormonal factors. There was no genotype-phenotype correlation. At the end of the follow-up, 80% of patients were ambulant and 87% of patients had no respiratory trouble in spite of severe relapses., (Copyright © 2011 Elsevier B.V. All rights reserved.)
Published: 2012
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41. [Major mechanisms involved in the synaptic transmission of the neuromuscular apparatus].

Author: Rigoard S, Wager M, Buffenoir K, Bauche S, Giot JP, Maixent JM, and Rigoard P
Subjects: Action Potentials physiology, Animals, Electrophysiology, Energy Metabolism physiology, Excitatory Postsynaptic Potentials physiology, Humans, Neuromuscular Junction metabolism, Neurotransmitter Agents metabolism, Neurotransmitter Agents physiology, Neuromuscular Junction physiology, Synaptic Transmission physiology
Abstract: Neuromuscular transmission results from a double signal transduction from electric impulses to chemical messengers, taking place at a highly differentiated region, the neuromuscular junction (NMJ). A nerve cell responds to a specific stimulus by modifications of its plasmic membrane properties, generating an action potential (AP). This electric signal is transmitted along the axon to the NMJ, where it induces the voltage-gated calcium channels to open. Intracellular calcium entry leads to acetylcholine release in the synaptic space at the active zones but all scientists do not consider it the major release factor. Acetylcholine binding with its receptor at the muscle membrane generates an endplate potential when the induced depolarization is greater than the sodium voltage channel opening threshold. Muscle AP causes a muscle contraction involving the three phases. This paper will successively review the electrophysiological and molecular mechanisms involved at the pre-, inter- and postsynaptic levels. The last part of the article will discuss electromechanical considerations directly affecting the mechanical properties of the muscle fiber, most particularly the factors influencing the predetermined involvement of motor units, motor neuron electrical properties determining responses to synaptic inputs and finally the impact of recruited motor neurons and their electrical impulse rates on muscle contraction strength and velocity.
Published: 2009
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42. [Pathophysiological, molecular and metabolic changes at the neuromuscular junction and the peripheral nerve after central nervous system lesions in humans].

Author: Rigoard P, Bauche S, Buffenoir K, Da Costa L, Boildieu N, Seguin F, Koenig J, Lapierre F, and Maixent JM
Subjects: Action Potentials physiology, Adult, Aged, Biological Transport, Active physiology, Electrophysiology, Female, Humans, Immunohistochemistry, Male, Microscopy, Confocal, Middle Aged, Muscle Spasticity etiology, Neuromuscular Junction ultrastructure, Peripheral Nerves ultrastructure, Peripheral Nervous System Diseases surgery, Receptors, Cholinergic drug effects, Receptors, Cholinergic physiology, Reverse Transcriptase Polymerase Chain Reaction, Schwann Cells pathology, Schwann Cells ultrastructure, Sodium-Potassium-Exchanging ATPase genetics, Sodium-Potassium-Exchanging ATPase physiology, Synaptic Transmission, Central Nervous System Diseases complications, Muscle Spasticity pathology, Muscle Spasticity surgery, Neuromuscular Junction metabolism, Neuromuscular Junction pathology, Peripheral Nerves metabolism, Peripheral Nerves pathology, Peripheral Nervous System Diseases etiology, Peripheral Nervous System Diseases pathology
Abstract: From the elaborate information processing that takes place in the brain to the contraction of skeletal muscles, the neurotransmission pathways involve, at least in part, (1) in tissue, Na+, K+-ATPase electrogenesis making action potential (AP) propagation possible and (2) in the cell, the synthesis, maturation, and renewal of an amazing number of molecules concentrated at the neuromuscular junction (NMJ). Our aim is to clarify CNS and peripheral nerve system (PNS) interactions by determining whether the partial motor recovery sometimes observed after a lesion of the first motoneuron is related to (1) changes in active transportation of the ions in peripheral nerve and/or muscle and (2) morphological and/or molecular changes at the NMJ, illustrating a dysfunction. Peripheral nerve surgery is proposed to some spastic patients who have recovered partially after CNS lesions to improve their gait. During these surgical procedures, the nerve and muscle samples that are usually resected can be collected and analyzed. Here, we report on eight patients who showed strictly similar motor recovery 2 years after massive CNS lesions and who underwent a selective tibial neurotomy for a spastic equinus foot. In these eight spastic patients, we performed a pathophysiological, molecular, and metabolic study of their neuromuscular junctions and peripheral nerves to characterize the dysfunction of the neuromuscular transmission after a permanent CNS injury.
Published: 2009
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43. [Structural and molecular organization, development and maturation of the neuromuscular junction].

Author: Rigoard P, Buffenoir K, Bauche S, Giot JP, Koenig J, Hantaï D, Lapierre F, and Wager M
Subjects: Animals, Humans, Motor Endplate physiology, Motor Neurons physiology, Muscle, Skeletal innervation, Neuromuscular Junction growth & development, Schwann Cells physiology, Neuromuscular Junction physiology, Neuromuscular Junction ultrastructure
Abstract: The neuromuscular junction is made up of the apposition of highly differentiated domains of three types of cell: the motor neuronal ending, the terminal Schwann cell and the muscle postsynaptic membrane. These three components are surrounded by a basal lamina, dedicated to molecular signal exchanges controlling neuromuscular formation, maturation and maintenance. This functional and structural differentiated complex conducts synaptic neurotransmission to the skeletal muscle fiber. Nerve and muscle have distinct roles in synaptic compartment differentiation. The initial steps of this differentiation and the motor endplate formation require several postsynaptic molecular agents including agrin, the tyrosine kinase receptor MuSK. Neuregulin is essentially involved in Schwann cell survival and guidance for axonal growth.
Published: 2009
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44. [Anatomy and physiology of the peripheral nerve].

Author: Rigoard P, Buffenoir K, Wager M, Bauche S, Giot JP, Robert R, and Lapierre F
Subjects: Animals, Axons physiology, Humans, Nerve Fibers, Myelinated physiology, Peripheral Nerves blood supply, Peripheral Nerves embryology, Peripheral Nervous System blood supply, Peripheral Nervous System embryology, Regional Blood Flow physiology, Schwann Cells physiology, Peripheral Nerves anatomy & histology, Peripheral Nerves physiology, Peripheral Nervous System anatomy & histology, Peripheral Nervous System physiology
Abstract: The peripheral nerve provides the pathway for motor, sensory and vegetative axons belonging to the peripheral nervous system. It transmits information between these neurons and their peripheral effectors in both directions (sensory receptors, skeletal muscles and viscera). The afferences to the periphery correspond to the nerve motor content, whereas efferences from the periphery, in charge of delivering information to the central integrators, correspond to nerve-sensitive content. This information support depends on intrinsic properties of the nerve itself. Recent advances in cellular and molecular biology have provided a better understanding of nerve physiology, which are reviewed here as an indispensable basis to the study of its pathology.
Published: 2009
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45. [Morphological study of CNS lesions and the consequences on rat neuromuscular junction and peripheral nerve using confocal laser scanning microscopy and Koelle's technique].

Author: Rigoard P, Buffenoir K, Chaillou M, Fares M, Da Costa L, Boildieu N, Seguin F, Lapierre F, Maixent JM, Bauche S, Koenig J, and Hantaï D
Subjects: Animals, Excitatory Postsynaptic Potentials, Female, Muscle, Skeletal innervation, Muscle, Skeletal pathology, Muscle, Skeletal ultrastructure, Neuromuscular Junction ultrastructure, Neuronal Plasticity physiology, Peripheral Nerves ultrastructure, Rats, Rats, Wistar, Spinal Cord Injuries pathology, Central Nervous System injuries, Central Nervous System pathology, Microscopy, Confocal methods, Neuromuscular Junction pathology, Peripheral Nerves pathology
Abstract: State of the Art: In humans, it is currently believed that peripheral nerves remain intact after central nervous system (CNS) injuries. This should lead us to observe a lack of amyotrophy in the peripheral projection areas of CNS damage. Nevertheless, the appearance of amyotrophy, described as underuse amyotrophy, is common in victims of CNS injury. Its pathophysiology remains poorly understood and is currently being debated. Amyotrophy could result directly from the structural deterioration of a nervous fiber in the muscular area corresponding to the CNS injury caused by neuromuscular junction (NMJ) changes., Aims of This Study: The aims of this study were to assess the repercussions of a CNS injury on the NMJ and peripheral nerve complex and to evaluate the involvement of peripheral nerves and NMJs in plasticity., Methodology: Peripheral nerve and muscle biopsies were collected from a group of 35 female Wistar rats that had previously undergone a thoracic spinal cord hemisection (15 rats at the T2 level (group 1), 15 rats at the T6 level (group 2), and 5 matched rats used as controls). We studied the localization and expression of the NMJ molecular components in muscle specimens by immunohistochemistry using confocal microscopy. We also searched for signs of nerve and muscle degeneration using light and electron microscopy., Results: We observed nonpathologic NMJs coexisting with completely denervated and partially reinnervated NMJs. We also found characteristics of embryonic behavior in rat axons secondary to axonal caliber distortions. Some authors associate this decrease in axonal activity with physiological denervation., Conclusion: This project was designed to improve the understanding of the mechanisms involved in the interactions between the first and second motoneurons after different types of CNS injuries, with variable functional repercussions. Our results strongly suggest that CNS injuries lead to both morphological and functional repercussions at the NMJ and the peripheral nerve.
Published: 2009
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46. [The anatomical substrate of muscle contractility].

Author: Rigoard P, Bauche S, Buffenoir K, Giot JP, Faure JP, Scepi M, Richer JP, Lapierre F, and Wager M
Subjects: Action Potentials physiology, Animals, Humans, Muscle Relaxation physiology, Muscle, Skeletal innervation, Myofibrils physiology, Muscle Contraction physiology, Muscle, Skeletal anatomy & histology, Muscle, Skeletal physiology
Abstract: Muscle fiber action participates in a true contractile machinery associated with noncontractile components providing mechanical stability. The myofibril, the muscle fiber subentity, has an extremely consistent architecture, composed of longitudinal cylindrical units called sarcomeres, the skeletal muscle length functional unit, a highly important place in the transduction of chemical signal into mechanical contractile energy, for the most part mediated by calcium. The sarcoplasmic reticulum is the other major component of muscle fiber and is dedicated to calcium storage, liberation and distribution to the fiber, under the influence of action potential propagation. This phenomenon is called excitation-contraction coupling. This paper explores muscle anatomy from its main embryologic stages of development to its histochemical specificity, including its molecular constitution, and details the main morphofunctional relations supporting muscle contraction.
Published: 2009
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47. [Molecular architecture of the sarcoplasmic reticulum and its role in the ECC].

Author: Rigoard P, Buffenoir K, Wager M, Bauche S, Giot JP, and Lapierre F
Subjects: Animals, Calcium Channels, L-Type physiology, Calcium Channels, L-Type ultrastructure, Electrophysiology, Humans, Ryanodine Receptor Calcium Release Channel physiology, Ryanodine Receptor Calcium Release Channel ultrastructure, Muscle Contraction physiology, Muscle, Skeletal physiology, Muscle, Skeletal ultrastructure, Sarcoplasmic Reticulum physiology, Sarcoplasmic Reticulum ultrastructure
Abstract: The sarcoplasmic reticulum (SR) plays a fundamental role in excitation-contraction coupling, which propagates the electric signal conversion along the muscle fiber's plasmic membrane to a mechanical event manifested as a muscle contraction. It plays a crucial role in calcium homeostasis and intracellular calcium storage control (storage, liberation and uptake) necessary for fiber muscle contraction and then relaxation. These functions take place at the triad, made up of individualized SR subdomains where the protein-specific organization provides efficient and fast coupling. Ryanodine receptors (RyR) and dihydropyridine receptors (DHPR) mainly act in calcium exchanges in the SR. This particular structural and molecular architecture must be correlated to its functional specificity.
Published: 2009
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48. [Tools and techniques dedicated to neuromuscular junction observation].

Author: Rigoard P, Buffenoir K, Bauche S, Fares M, Koenig J, Hantaï D, Giot JP, Seguin F, Huze C, Schaeffer L, and Maixent JM
Subjects: Animals, Humans, Muscle, Skeletal innervation, Muscle, Skeletal physiology, Neuromuscular Junction metabolism, Neuromuscular Junction ultrastructure, Synaptic Transmission, Electrophysiology methods, Neuromuscular Junction physiology
Abstract: A few decades ago, the neuromuscular junction (NMJ) concept was reduced to two elements: the nerve ending and the facing muscular zone. This description has since changed substantially based on recent studies conducted on the molecular aspects of neurotransmission. The aim of this paper is to provide a synthetic view of the major morphological, molecular and electrophysiological tools used in the analysis of NMJ architecture and its functional characterization.
Published: 2009
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49. [Synapse formation and regeneration].

Author: d'Houtaud S, Sztermer E, Buffenoir K, Giot JP, Wager M, Bauche S, Lapierre F, and Rigoard P
Subjects: Animals, Cell Differentiation, Excitatory Postsynaptic Potentials physiology, Humans, Motor Neurons physiology, Neurotransmitter Agents physiology, Synapses metabolism, Synaptic Transmission physiology, Nerve Regeneration physiology, Synapses physiology
Abstract: Synapse formation is probably the key process in neural development allowing signal transmission between nerve cells. As an interesting model of synapse maturation, we considered first the neuromuscular junction (NMJ), whose development is particularly dependent on intercellular interactions between the motor nerve and the skeletal muscle. Nerve and muscle have distinct roles in synaptic compartment differentiation. The initial steps of this differentiation and motor endplate formation require several postsynaptic molecular agents including agrin, the tyrosine kinase receptor MuSK and rapsyn. The agrin or motoneuron dependence of this process continues to be debated while the following steps of axonal growth and postsynaptic apparatus maintenance essentially depend on neuronal agrin and a neuron-specific signal dispersing ectopic AChR aggregate remainders, possibly mediated by acetylcholine itself. Neuregulin is essentially involved in Schwann's cell survival and guidance for axonal growth. In this paper, we will discuss the similarities between Central Nervous System (CNS) synaptic formation and Motor innervation. The limited ability of the CNS to create new synapses after nervous system injury will be then discussed with a final consideration of some new strategies elaborated to circumvent the limitations of lesion extension processes.
Published: 2009
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