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

Fingerprint

Spinal Muscular Atrophy
Sensory Receptor Cells
Charcot-Marie-Tooth Disease
Amino Acyl-tRNA Synthetases
Ubiquitination
Motor Neurons
Ubiquitin
Spinal Cord
Enzymes

Keywords

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

Cite this

Shorrock, H. K., van der Hoorn, D., Boyd, P. J., Llavero Hurtado, M., Lamont, D. J., Wirth, B., ... 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
Shorrock, Hannah K. ; van der Hoorn, Dinja ; Boyd, Penelope J. ; Llavero Hurtado, Maica ; Lamont, Douglas J. ; Wirth, Brunhilde ; Sleigh, James N. ; Schiavo, Giampietro ; Wishart, Thomas M. ; Groen, Ewout J. N. ; Gillingwater, Thomas H. / UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy. In: Brain. 2018 ; Vol. 141, No. 10. pp. 2878-2894.
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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.",
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note = "This work was supported by funding from the Euan MacDonald Centre for Motor Neurone Disease Research, SMA Europe, the SMA Trust UK Consortium (all to T.H.G.), the Wellcome Trust (to J.N.S., E.J.N.G and T.H.G), the Darwin foundation and the BBSRC (to T.M.W), the European Union’s Horizon 2020 Research and Innovation programme under grant agreement 739572, the Wellcome Trust Senior Investigator Award (107116/Z/15/Z) and a UK Dementia Research Institute Foundation award (all to G.S.).",
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Shorrock, HK, van der Hoorn, D, Boyd, PJ, Llavero Hurtado, M, Lamont, DJ, Wirth, B, Sleigh, JN, Schiavo, G, Wishart, TM, Groen, EJN & Gillingwater, TH 2018, 'UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy', Brain, vol. 141, no. 10, pp. 2878-2894. https://doi.org/10.1093/brain/awy237

UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy. / Shorrock, Hannah K.; van der Hoorn, Dinja; Boyd, Penelope J.; Llavero Hurtado, Maica; Lamont, Douglas J.; Wirth, Brunhilde; Sleigh, James N.; Schiavo, Giampietro; Wishart, Thomas M.; Groen, Ewout J. N. (Lead / Corresponding author); Gillingwater, Thomas H.

In: Brain, Vol. 141, No. 10, 01.10.2018, p. 2878-2894.

Research output: Contribution to journalArticle

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AU - Shorrock, Hannah K.

AU - van der Hoorn, Dinja

AU - Boyd, Penelope J.

AU - Llavero Hurtado, Maica

AU - Lamont, Douglas J.

AU - Wirth, Brunhilde

AU - Sleigh, James N.

AU - Schiavo, Giampietro

AU - Wishart, Thomas M.

AU - Groen, Ewout J. N.

AU - Gillingwater, Thomas H.

N1 - This work was supported by funding from the Euan MacDonald Centre for Motor Neurone Disease Research, SMA Europe, the SMA Trust UK Consortium (all to T.H.G.), the Wellcome Trust (to J.N.S., E.J.N.G and T.H.G), the Darwin foundation and the BBSRC (to T.M.W), the European Union’s Horizon 2020 Research and Innovation programme under grant agreement 739572, the Wellcome Trust Senior Investigator Award (107116/Z/15/Z) and a UK Dementia Research Institute Foundation award (all to G.S.).

PY - 2018/10/1

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N2 - 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.

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KW - motor neuron disease

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Shorrock HK, van der Hoorn D, Boyd PJ, Llavero Hurtado M, Lamont DJ, Wirth B et al. UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy. Brain. 2018 Oct 1;141(10):2878-2894. https://doi.org/10.1093/brain/awy237