期刊
BRAIN
卷 141, 期 -, 页码 2878-2894出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awy237
关键词
motor neuron disease; spinal muscular atrophy; Charcot-Marie-Tooth disease; UBA1; GARS
资金
- Euan MacDonald Centre for Motor Neurone Disease Research
- SMA Europe
- SMA Trust UK Consortium
- Wellcome Trust
- Darwin foundation
- BBSRC
- European Union [739572]
- Wellcome Trust [107116/Z/15/Z]
- UK Dementia Research Institute Foundation
- BBSRC [BBS/E/D/20251969, BBS/E/D/10002071] Funding Source: UKRI
- MRC [UKDRI-1005] Funding Source: UKRI
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 CharcotMarie-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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