title: Neuregulin-1 promotes functional improvement by enhancing collateral sprouting in SOD1(G93A) ALS mice and after partial muscle denervation.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motoneurons, which is preceded by loss of neuromuscular connections in a "dying back" process. Neuregulin-1 (Nrg1) is a neurotrophic factor essential for the development and maintenance of neuromuscular junctions, and Nrg1 receptor ErbB4 loss-of-function mutations have been reported as causative for ALS. Our main goal was to investigate the role of Nrg1 type I (Nrg1-I) in SOD1(G93A) mice muscles. We overexpressed Nrg1-I by means of an adeno-associated viral (AAV) vector, and investigated its effect by means of neurophysiological techniques assessing neuromuscular function, as well as molecular approaches (RT-PCR, western blot, immunohistochemistry, ELISA) to determine the mechanisms underlying Nrg1-I action. AAV-Nrg1-I intramuscular administration promoted motor axon collateral sprouting by acting on terminal Schwann cells, preventing denervation of the injected muscles through Akt and ERK1/2 pathways. We further used a model of muscle partial denervation by transecting the L4 spinal nerve. AAV-Nrg1-I intramuscular injection enhanced muscle reinnervation by collateral sprouting, whereas administration of lapatinib (ErbB receptor inhibitor) completely blocked it. We demonstrated that Nrg1-I plays a crucial role in the collateral reinnervation process, opening a new window for developing novel ALS therapies for functional recovery rather than preservation.
authors.affiliation: Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain; Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Renzo
authors.initials: R
authors.lastname: Mancuso
authors.affiliation: Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Martínez-Muriana
authors.affiliation: Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Leiva
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Gregorio
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Ariza
authors.affiliation: Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Morell
authors.affiliation: Unidad de ELA, Servicio de Neurología, Instituto de Investigación Biomédica, Hospital 12 de Octubre "i+12", Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Esteban-Pérez
authors.affiliation: Unidad de ELA, Servicio de Neurología, Instituto de Investigación Biomédica, Hospital 12 de Octubre "i+12", Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: García-Redondo
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Kresgae Hearing Research Institute, University of Michigan, Michigan, US.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Calvo
authors.affiliation: Unidad de ELA, Servicio de Neurología, Instituto de Investigación Biomédica, Hospital 12 de Octubre "i+12", Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Atencia-Cibreiro
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Kresgae Hearing Research Institute, University of Michigan, Michigan, US.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Corfas
authors.affiliation: Laboratorio de Genética y Bioquímica (LAGENBIO), Facultad de Veterinaria, Instituto Agroalimentario de Aragón (IA2), Instituto de Investigación Sanitaria Aragón, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Osta
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Assumpció
authors.initials: A
authors.lastname: Bosch
authors.affiliation: Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain. Electronic address: xavier.navarro@uab.cat.
authors.forename: Xavier
authors.initials: X
authors.lastname: Navarro
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D000077341:Lapatinib; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009121:Muscle Denervation / Q000379:methods; D020890:Neuregulin-1 / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects; D009469:Neuromuscular Junction / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D020890:Neuregulin-1; D011799:Quinazolines; D000077341:Lapatinib; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; Collateral sprouting; Motoneuron; Neuregulin-1; Neuromuscular junction