UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy

TY - JOUR

T1 - UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy

AU - Shorrock, Hannah K.

AU - van der Hoorn, Dinja

AU - Boyd, Penelope J.

AU - Llavero Hurtado, Maica

AU - Lamont, Douglas J.

AU - Wirth, Brunhilde

AU - Sleigh, James N.

AU - Schiavo, Giampietro

AU - Wishart, Thomas M.

AU - Groen, Ewout J. N.

AU - Gillingwater, Thomas H.

N1 - This work was supported by funding from the Euan MacDonald Centre for Motor Neurone Disease Research, SMA Europe, the SMA Trust UK Consortium (all to T.H.G.), the Wellcome Trust (to J.N.S., E.J.N.G and T.H.G), the Darwin foundation and the BBSRC (to T.M.W), the European Union’s Horizon 2020 Research and Innovation programme under grant agreement 739572, the Wellcome Trust Senior Investigator Award (107116/Z/15/Z) and a UK Dementia Research Institute Foundation award (all to G.S.).

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

KW - motor neuron disease

KW - spinal muscular atrophy

KW - Charcot-Marie-Tooth disease

KW - UBA1

KW - GARS

U2 - 10.1093/brain/awy237

DO - 10.1093/brain/awy237

M3 - Article

C2 - 30239612

SN - 0006-8950

VL - 141

SP - 2878

EP - 2894

JO - Brain

JF - Brain

IS - 10

ER -