1. UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy.
- Author
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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, and Gillingwater TH
- Subjects
- Animals, Ganglia, Spinal metabolism, Ganglia, Spinal pathology, Gene Expression Regulation physiology, HEK293 Cells, Humans, Mice, Motor Neurons metabolism, Motor Neurons pathology, Muscular Atrophy, Spinal metabolism, Neural Pathways metabolism, Sensory Receptor Cells metabolism, Sensory Receptor Cells pathology, Signal Transduction physiology, Spinal Cord metabolism, Spinal Cord pathology, Amino Acyl-tRNA Synthetases metabolism, Muscular Atrophy, Spinal pathology, Neural Pathways pathology, Ubiquitin-Activating Enzymes metabolism
- 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.
- Published
- 2018
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