title: Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice.
abstract: Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study, we explore the effects of one such transcript-Z+Agrin-known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice increases muscle fiber size, enhances the post-synaptic NMJ area, reduces the abnormal accumulation of intermediate filaments in nerve terminals of the neuromuscular synapse and improves the innervation of muscles. While these effects are independent of changes in SMN levels or increases in motor neuron numbers they nevertheless have a significant effect on the overall disease phenotype, enhancing mean survival in severely affected SMA model mice by ∼40%. We conclude that Agrin is an important target of the SMN protein and that mitigating NMJ defects may be one strategy in treating human spinal muscular atrophy.
authors.affiliation: Department of Pathology and Cell Biology.|Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Pathology and Cell Biology.|Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Caine
authors.affiliation: Department of Pathology and Cell Biology.|Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Awano
authors.affiliation: Center for Brain Research.|Institute of Immunology, Medical University of Vienna, 1090 Vienna.
authors.forename: Ruth
authors.initials: R
authors.lastname: Herbst
authors.affiliation: Department of Pathology and Cell Biology.|Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA.|Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Umrao R
authors.initials: UR
authors.lastname: Monani
mesh_terms: D018171:Agrin / Q000235:genetics* / Q000378:metabolism; D017398:Alternative Splicing; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009468:Neuromuscular Diseases / Q000235:genetics / Q000378:metabolism; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics; D013569:Synapses / Q000378:metabolism
chemical_list: D018171:Agrin; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein