title: The neuroprotective factor Wld(s) fails to mitigate distal axonal and neuromuscular junction (NMJ) defects in mouse models of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a common autosomal recessive neurodegenerative disorder in humans. Amongst the earliest signs of neurodegeneration are severe and progressive defects of the neuromuscular synapse. These defects, characterized by poor terminal arborization and immature motor endplates, presumably result in a loss of functional synapses. The slow Wallerian degeneration (Wld(s)) mutation in rodents has been shown to have a protective effect on mouse models of motor neuron disease by retarding axonal die-back and preventing neuromuscular synapse loss. In this study we tested the effects of the Wld(s) mutation on the disease phenotype of SMA model mice. Consistent with previous reports, the mutation slows axon and neuromuscular synapse loss following nerve injury in wild-type as well as in SMA mice. However, the synaptic defects found in severely affected SMA patients and model mice persist in the double (Wld(s);SMA) mutants. No delay in disease onset was observed and survival was not significantly altered. Finally, Wld(s) had no effect on the striking phrenic nerve projection defects that we discovered in SMA model mice. Our results indicate that the reported protective effects of Wld(s) are insufficient to mitigate the neuromuscular phenotype due to reduced SMN protein, and that the mechanisms responsible for distal defects of the motor unit in SMA are unlikely to be similar to those causing neurodegeneration in genetic mutants such as the pmn mouse which is partially rescued by the Wld(s) protein.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kariya
authors.forename: Rina
authors.initials: R
authors.lastname: Mauricio
authors.forename: Ya
authors.initials: Y
authors.lastname: Dai
authors.forename: Umrao R
authors.initials: UR
authors.lastname: Monani
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology* / Q000502:physiology; D001835:Body Weight / Q000235:genetics; D002038:Bungarotoxins / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009134:Muscular Atrophy, Spinal / Q000150:complications / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology / Q000517:prevention & control*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D020511:Neuromuscular Junction Diseases / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D016019:Survival Analysis; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics
chemical_list: D002038:Bungarotoxins; D009419:Nerve Tissue Proteins; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; C442580:Wld protein, mouse