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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.

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


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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