Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy

Gillian Hunter, Rachael A. Powis, Ross A. Jones, Ewout J.N. Groen, Hannah K. Shorrock, Fiona M. Lane, Yinan Zheng, Diane L. Sherman, Peter J. Brophy, Thomas H. Gillingwater*

*Corresponding author for this work

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Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, primarily affecting lower motor neurons. Recent evidence from SMA and related conditions suggests that glial cells can influence disease severity. Here, we investigated the role of glial cells in the peripheral nervous system by creating SMA mice selectively overexpressing SMN in myelinating Schwann cells (Smn-/-;SMN2tg/0;SMN1SC). Restoration of SMN protein levels restricted solely to Schwann cells reversed myelination defects, significantly improved neuromuscular function and ameliorated neuromuscular junction pathology in SMA mice. However, restoration of SMN in Schwann cells had no impact on motor neuron soma loss from the spinal cord or ongoing systemic and peripheral pathology. This study provides evidence for a defined, intrinsic contribution of glial cells to SMA disease pathogenesis and suggests that therapies designed to include Schwann cells in their target tissues are likely to be required in order to rescue myelination defects and associated disease symptoms.
Original languageEnglish
Pages (from-to)2853-2861
Number of pages9
JournalHuman Molecular Genetics
Volume25
Issue number13
Early online date11 May 2016
DOIs
Publication statusPublished - 1 Jul 2016

Keywords

  • SMA
  • Schwann cell
  • motor neurons
  • spinal muscular atrophy
  • neuromuscular junction
  • mice
  • pathology
  • spinal cord
  • myelination
  • neuromuscular function

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    Hunter, G., Powis, R. A., Jones, R. A., Groen, E. J. N., Shorrock, H. K., Lane, F. M., Zheng, Y., Sherman, D. L., Brophy, P. J., & Gillingwater, T. H. (2016). Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy. Human Molecular Genetics, 25(13), 2853-2861. https://doi.org/10.1093/hmg/ddw141