1. UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy
- Author
-
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, and Thomas H, Gillingwater
- Subjects
Motor Neurons ,Sensory Receptor Cells ,Ubiquitin-Activating Enzymes ,Original Articles ,Charcot-Marie-Tooth disease ,Amino Acyl-tRNA Synthetases ,Muscular Atrophy, Spinal ,Mice ,HEK293 Cells ,Gene Expression Regulation ,Spinal Cord ,Ganglia, Spinal ,Neural Pathways ,motor neuron disease ,GARS ,Animals ,Humans ,Signal Transduction ,spinal muscular atrophy ,UBA1 - Abstract
Deafferentation of motor neurons as a result of defective sensory-motor connectivity in the spinal cord is an important early event in spinal muscular atrophy. Shorrock et al. report that this process is reversible in mice and results from disruption of a novel UBA1/GARS pathway that controls sensory neuron fate., 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