title: The spinal muscular atrophy mouse model, SMAΔ7, displays altered axonal transport without global neurofilament alterations.
abstract: Spinal muscular atrophy (SMA) is a neurodegenerative disease resulting from decreased levels of survival motor neuron 1 (SMN1) protein. Reduced SMN1 levels are linked to pathology at neuromuscular junctions (NMJs), which includes decreased vesicle density and organization, decreased quantal release, increased endplate potential duration, and neurofilament (NF) accumulations. This work presents a first study towards defining molecular alterations that may lead to the development of NMJ pathology in SMA. Fast, anterograde transport of synaptic vesicle 2 (SV2-c) and synaptotagmin (Syt1) proteins was reduced 2 days prior to the observed decrease in synaptic vesicle density. Moreover, reduced accumulation of SV2-c or Syt1 was not due to reduced protein expression or reduced kinesin activity. Dynein levels were reduced at times that are consistent with NF accumulations at NMJs. Furthermore, NF distribution, from cell body to sciatic nerve, appeared normal in SMA∆7 mice. Taken together, these results suggest that reduced axonal transport may provide a mechanistic explanation for reduced synaptic vesicle density and concomitant synaptic transmission defects, while providing evidence that suggests NF accumulations result from local NMJ alterations to NFs.
authors.affiliation: Division of Biological Sciences, University of Missouri-Columbia, Columbia, MO 65211, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Dale
authors.forename: Hailian
authors.initials: H
authors.lastname: Shen
authors.forename: Devin M
authors.initials: DM
authors.lastname: Barry
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Garcia
authors.forename: Ferrill F
authors.initials: FF
authors.lastname: Rose
authors.forename: Christian L
authors.initials: CL
authors.lastname: Lorson
authors.forename: Michael L
authors.initials: ML
authors.lastname: Garcia
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000473:pathology*; D001692:Biological Transport / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009134:Muscular Atrophy, Spinal / Q000150:complications / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D055532:SMN Complex Proteins / Q000235:genetics*; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D020426:Sciatic Neuropathy / Q000378:metabolism / Q000473:pathology; D050857:Synaptotagmins / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D055532:SMN Complex Proteins; C489614:Sv2a protein, mouse; D050857:Synaptotagmins