UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy

Hannah K. Shorrock, Dinja van der Hoorn, Penelope J. Boyd, Maica Llavero Hurtado, Douglas J. Lamont, Brunhilde Wirth, James N. Sleigh, Giampietro Schiavo, Thomas M. Wishart, Ewout J. N. Groen (Lead / Corresponding author), Thomas H. Gillingwater

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Abstract

Deafferentation of motor neurons as a result of defective sensory-motor connectivity is a critical early event in the pathogenesis of spinal muscular atrophy, but the underlying molecular pathways remain unknown. We show that restoration of ubiquitin-like modifier-activating enzyme 1 (UBA1) was sufficient to correct sensory-motor connectivity in the spinal cord of mice with spinal muscular atrophy. Aminoacyl-tRNA synthetases, including GARS, were identified as downstream targets of UBA1. Regulation of GARS by UBA1 occurred via a non-canonical pathway independent of ubiquitylation. Dysregulation of UBA1/GARS pathways in spinal muscular atrophy mice disrupted sensory neuron fate, phenocopying GARS-dependent defects associated with Charcot-Marie-Tooth disease. Sensory neuron fate was corrected following restoration of UBA1 expression and UBA1/GARS pathways in spinal muscular atrophy mice. We conclude that defective sensory motor connectivity in spinal muscular atrophy results from perturbations in a UBA1/GARS pathway that modulates sensory neuron fate, thereby highlighting significant molecular and phenotypic overlap between spinal muscular atrophy and Charcot-Marie-Tooth disease.

Original languageEnglish
Pages (from-to)2878-2894
Number of pages17
JournalBrain
Volume141
Issue number10
Early online date19 Sep 2018
DOIs
Publication statusPublished - 1 Oct 2018

Keywords

  • motor neuron disease
  • spinal muscular atrophy
  • Charcot-Marie-Tooth disease
  • UBA1
  • GARS

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    Shorrock, H. K., van der Hoorn, D., Boyd, P. J., Llavero Hurtado, M., Lamont, D. J., Wirth, B., Sleigh, J. N., Schiavo, G., Wishart, T. M., Groen, E. J. N., & Gillingwater, T. H. (2018). UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy. Brain, 141(10), 2878-2894. https://doi.org/10.1093/brain/awy237