Neuregulin-1 promotes functional improvement by enhancing collateral sprouting in SOD1G93A ALS mice and after partial muscle denervation

Renzo Mancuso, Anna Martínez-Muriana, Tatiana Leiva, David Gregorio, Lorena Ariza, Marta Morell, Jesús Esteban-Pérez, Alberto García-Redondo, Ana C. Calvo, Gabriela Atencia-Cibreiro, Gabriel Corfas, Rosario Osta, Assumpció Bosch, Xavier Navarro

Research output: Contribution to journalArticleResearchpeer-review

32 Citations (Scopus)

Abstract

© 2016 Elsevier Inc. 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 SOD1G93A 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.
Original languageEnglish
Pages (from-to)168-178
JournalNeurobiology of Disease
Volume95
DOIs
Publication statusPublished - 1 Nov 2016

Keywords

  • Amyotrophic lateral sclerosis
  • Collateral sprouting
  • Motoneuron
  • Neuregulin-1
  • Neuromuscular junction

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