title: Defects in neuromuscular junction remodelling in the Smn(2B/-) mouse model of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease caused by mutations and deletions within the survival motor neuron 1 (SMN1) gene. Although other tissues may be involved, motor neurons remain primary pathological targets, with loss of neuromuscular junctions (NMJs) representing an early and significant event in pathogenesis. Although defects in axonal outgrowth and pathfinding have been observed in cell culture and in lower organisms upon Smn depletion, developmental defects in mouse models have been less obvious. Here, we have employed the Smn(2B/-) mouse model to investigate NMJ remodelling during SMA pathology, induced reinnervation, and paralysis. We show that whilst NMJs are capable of remodelling during pathogenesis, there is a marked reduction in paralysis-induced remodelling and in the nerve-directed re-organisation of acetylcholine receptors. This reduction in remodelling potential could not be attributed to a decreased rate of axonal growth. Finally, we have identified a loss of terminal Schwann cells which could contribute to the defects in remodelling/maintenance observed. Our work demonstrates that there are specific defects in NMJ remodelling in an intermediate SMA mouse model, which could contribute to or underlie pathogenesis in SMA. The development of strategies that can promote the remodelling potential of NMJs may therefore be of significant benefit to SMA patients.
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6.
authors.forename: Lyndsay M
authors.initials: LM
authors.lastname: Murray
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6.
authors.forename: Ariane
authors.initials: A
authors.lastname: Beauvais
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6.
authors.forename: Kunal
authors.initials: K
authors.lastname: Bhanot
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5; Department of Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5. Electronic address: rkothary@ohri.ca.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000473:pathology / Q000502:physiology; D019274:Botulinum Toxins, Type A; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D009134:Muscular Atrophy, Spinal / Q000473:pathology* / Q000503:physiopathology*; D009416:Nerve Regeneration / Q000502:physiology; D009469:Neuromuscular Junction / Q000473:pathology* / Q000503:physiopathology*; D009473:Neuronal Plasticity / Q000502:physiology; D010243:Paralysis / Q000473:pathology / Q000503:physiopathology; D012583:Schwann Cells / Q000473:pathology / Q000502:physiology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D013979:Tibial Nerve / Q000293:injuries / Q000473:pathology / Q000503:physiopathology
chemical_list: C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D019274:Botulinum Toxins, Type A; D000109:Acetylcholine