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The spinal muscular atrophy mouse model, SMAΔ7, displays altered axonal transport without global neurofilament alterations

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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.

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Acknowledgments

This work was supported by Grants from National Institutes of Health [Grant number NS060073] and Charcot-Marie-Tooth Association [Grant number C00014627] and University of Missouri Research Board to MLG and by Grants from National Institutes of Health [Grant numbers R01HD054413 and R01NS041584] to CLL. Salary support for MLG was provided by the University of Missouri-Columbia and the C.S. Bond Life Sciences Center. JMD was supported by an ARRA supplement to T32 GM008396. HS was supported by Charcot-Marie-Tooth Association [Grant number C00014627] to MLG. DMB was supported by both the C.S. Bond Life Sciences Fellowship Program and the Graduate Assistance in Areas of National Need Fellowship Program. We thank the following: Electron Microscopy Core Facility at the University of Missouri for assistance with tissue preparation and with electron microscopic analysis, Mr. Steve Lamont for writing the scripts used in automated determination of numbers of NFs in assigned groups for nearest neighbor distance profiles, and Dr. Emmanual Liscum and Dr. David Schulz for comments and insights that improved this manuscript.

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Author notes

  1. Hailian Shen

    Present address: Department of Neurology, LRB 670Z, University of Massachusetts Medical School, Worcester, MA, 01605, USA

Authors and Affiliations

  1. Division of Biological Sciences, University of Missouri-Columbia, Columbia, MO, 65211, USA

    Jeffrey M. Dale, Devin M. Barry & Michael L. Garcia

  2. 345 C.S. Bond Life Sciences Center, University of Missouri-Columbia, 1201 Rollins Rd, Columbia, MO, 65211, USA

    Jeffrey M. Dale, Hailian Shen, Devin M. Barry & Virginia B. Garcia

  3. Veterinary Pathology/Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, MO, 65211, USA

    Ferrill F. Rose Jr & Christian L. Lorson

  4. 403 C.S. Bond Life Sciences Center, University of Missouri-Columbia, 1201 Rollins Rd, Columbia, MO, 65211, USA

    Ferrill F. Rose Jr

  5. 471G C.S. Bond Life Sciences Center, University of Missouri-Columbia, 1201 Rollins Rd, Columbia, MO, 65211, USA

    Christian L. Lorson

  6. 340C C.S. Bond Life Sciences Center, University of Missouri-Columbia, 1201 Rollins Rd, Columbia, MO, 65211, USA

    Michael L. Garcia

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  1. Jeffrey M. Dale
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Correspondence to Michael L. Garcia.

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Dale, J.M., Shen, H., Barry, D.M. et al. The spinal muscular atrophy mouse model, SMAΔ7, displays altered axonal transport without global neurofilament alterations. Acta Neuropathol 122, 331–341 (2011). https://doi.org/10.1007/s00401-011-0848-5

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  • DOI: https://doi.org/10.1007/s00401-011-0848-5

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