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UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy.
- Source :
-
Brain : a journal of neurology [Brain] 2018 Oct 01; Vol. 141 (10), pp. 2878-2894. - Publication Year :
- 2018
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2156
- Volume :
- 141
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Brain : a journal of neurology
- Publication Type :
- Academic Journal
- Accession number :
- 30239612
- Full Text :
- https://doi.org/10.1093/brain/awy237