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Pàgina inicial > Articles > Articles publicats > Neuregulin-1 promotes functional improvement by enhancing collateral sprouting in SOD1G93A ALS mice and after partial muscle denervation |
Data: | 2016 |
Resum: | 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. |
Ajuts: | Instituto de Salud Carlos III PI14/00947 Instituto de Salud Carlos III PI10/00092 Instituto de Salud Carlos III PI14/00088 Instituto de Salud Carlos III PI111532 Instituto de Salud Carlos III PS09720 Instituto de Salud Carlos III PS09730 Ministerio de Economía y Competitividad SAF2009-12495 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014SGR-1354 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014SGR-201 |
Nota: | Altres ajuts: Fundació La Marato-TV3(TV3201428-10), AFM-Telethon (Nrg14ALS) |
Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades. |
Llengua: | Anglès |
Document: | Article ; recerca ; Versió acceptada per publicar |
Matèria: | Neuregulin-1 ; Amyotrophic lateral sclerosis ; Neuromuscular junction ; Motoneuron ; Collateral sprouting |
Publicat a: | Neurobiology of disease, Vol. 95 (November 2016) , p. 168-178, ISSN 0969-9961 |
Post-Print 34 p, 687.0 KB |