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Brain. 2018 Oct 1;141(10):2878-2894. doi: 10.1093/brain/awy237.

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

Author information

1
Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK.
2
Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh, UK.
3
Roslin Institute, Royal (Dick) School of Veterinary Science, University of Edinburgh, UK.
4
FingerPrints Proteomics Facility, University of Dundee, UK.
5
Institute of Human Genetics, Center for Molecular Medicine Cologne, Institute for Genetics and Center for Rare Diseases Cologne, University of Cologne, Germany.
6
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, UK.
7
Discoveries Centre for Regenerative and Precision Medicine, University College London Campus, London, UK.
8
UK Dementia Research Institute at UCL, London, UK.

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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