title: Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients.
abstract: OBJECTIVE
  Data from mouse models of amyotrophic lateral sclerosis (ALS) suggest early morphological changes in neuromuscular junctions (NMJs), with loss of nerve-muscle contact. Overexpression of the neurite outgrowth inhibitor Nogo-A in muscle may play a role in this loss of endplate innervation.
  
  
  METHODS
  We used confocal and electron microscopy to study the structure of the NMJs in muscle samples collected from nine ALS patients (five early-stage patients and four long-term survivors). We correlated the morphological results with clinical and electrophysiological data, and with Nogo-A muscle expression level.
  
  
  RESULTS
  Surface electromyography assessment of neuromuscular transmission was abnormal in 3/9 ALS patients. The postsynaptic apparatus was morphologically altered for almost all NMJs (n = 430) analyzed using confocal microscopy. 19.7% of the NMJs were completely denervated (fragmented synaptic gutters and absence of nerve terminal profile). The terminal axonal arborization was usually sparsely branched and 56.8% of innervated NMJs showed a typical reinnervation pattern. Terminal Schwann cell (TSC) morphology was altered with extensive cytoplasmic processes. A marked intrusion of TSCs in the synaptic cleft was seen in some cases, strikingly reducing the synaptic surface available for neuromuscular transmission. Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome.
  
  
  CONCLUSIONS
  Our results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients. Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression.
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France ; APHP, Hôpital Pitié-Salpêtrière, Département des Maladies du Système Nerveux, Centre référent SLA Paris, France ; APHP, INSERM, ICM, Centre d'Investigation Clinique Pitié Neurosciences, CIC-1422, Département des Maladies du Système Nerveux, Hôpital Pitié-Salpêtrière Paris, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bruneteau
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bauché
authors.affiliation: Université de Strasbourg, UMR_S 1118 Strasbourg, France ; INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence Strasbourg, France.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Gonzalez de Aguilar
authors.affiliation: Unité de Morphologie Neuromusculaire, Institut de Myologie, Hôpital Pitié-Salpêtrière Paris, France ; APHP, Hôpital Pitié-Salpêtrière, Centre de référence de pathologie neuromusculaire Paris-Est, Institut de Myologie Paris, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Brochier
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mandjee
authors.affiliation: AP-HP, Hôpital Pitié-Salpêtrière, Unité de Recherche Clinique Paris, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Tanguy
authors.affiliation: Université de Strasbourg, UMR_S 1118 Strasbourg, France ; INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence Strasbourg, France.
authors.forename: Ghulam
authors.initials: G
authors.lastname: Hussain
authors.affiliation: APHP, Hôpital Pitié-Salpêtrière, Centre de référence de pathologie neuromusculaire Paris-Est, Institut de Myologie Paris, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Behin
authors.affiliation: APHP, Hôpital Pitié-Salpêtrière, Service d'Orthopédie Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Khiami
authors.affiliation: APHP, Hôpital Pitié-Salpêtrière, Service d'Orthopédie Paris, France.
authors.forename: Elhadi
authors.initials: E
authors.lastname: Sariali
authors.affiliation: APHP, Hôpital Pitié-Salpêtrière, Département d'Anesthésie-Réanimation Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hell-Remy
authors.affiliation: APHP, Hôpital Pitié-Salpêtrière, Département des Maladies du Système Nerveux, Centre référent SLA Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Salachas
authors.affiliation: APHP, Hôpital Pitié-Salpêtrière, Département des Maladies du Système Nerveux, Centre référent SLA Paris, France.
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Pradat
authors.affiliation: APHP, Hôpital Pitié-Salpêtrière, Département des Maladies du Système Nerveux, Centre référent SLA Paris, France.
authors.forename: Lucette
authors.initials: L
authors.lastname: Lacomblez
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Nicole
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.affiliation: Unité de Morphologie Neuromusculaire, Institut de Myologie, Hôpital Pitié-Salpêtrière Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Fardeau
authors.affiliation: Université de Strasbourg, UMR_S 1118 Strasbourg, France ; INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence Strasbourg, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Loeffler
authors.affiliation: APHP, Hôpital Pitié-Salpêtrière, Département des Maladies du Système Nerveux, Centre référent SLA Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France ; APHP, Hôpital Pitié-Salpêtrière, Centre de référence de pathologie neuromusculaire Paris-Est, Institut de Myologie Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Fournier
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France.
authors.forename: Jeanine
authors.initials: J
authors.lastname: Koenig
authors.affiliation: Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France ; APHP, Hôpital Pitié-Salpêtrière, Centre de référence de pathologie neuromusculaire Paris-Est, Institut de Myologie Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hantaï