Shorrock, H;
van der Hoorn, D;
Boyd, P;
Hurtado, M;
Lamont, D;
Wirth, B;
Sleigh, JN;
... Gillingwater, TH; + view all
(2018)
UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy.
Brain: A Journal of Neurology
, 141
(10)
pp. 2878-2894.
10.1093/brain/awy237.
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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.
| Type: | Article |
|---|---|
| Title: | UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/brain/awy237 |
| Publisher version: | https://doi.org/10.1093/brain/awy237 |
| Language: | English |
| Additional information: | © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/by/4.0/). |
| Keywords: | motor neuron disease, spinal muscular atrophy, Charcot-Marie-Tooth disease, UBA1, GARS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10056848 |
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