Universität zu Köln

Shorrock, Hannah K., van der Hoorn, Dinja, Boyd, Penelope J., Hurtado, Maica Llavero, Lamont, Douglas J., Wirth, Brunhilde ORCID: 0000-0003-4051-5191, Sleigh, James N. ORCID: 0000-0002-3782-9045, Schiavo, Giampietro, Wishart, Thomas M., Groen, Ewout J. N. and Gillingwater, Thomas H. (2018). UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy. Brain, 141. S. 2878 - 2895. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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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 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Shorrock, Hannah K. UNSPECIFIED UNSPECIFIED UNSPECIFIED van der Hoorn, Dinja UNSPECIFIED UNSPECIFIED UNSPECIFIED Boyd, Penelope J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hurtado, Maica Llavero UNSPECIFIED UNSPECIFIED UNSPECIFIED Lamont, Douglas J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirth, Brunhilde UNSPECIFIED orcid.org/0000-0003-4051-5191 UNSPECIFIED Sleigh, James N. UNSPECIFIED orcid.org/0000-0002-3782-9045 UNSPECIFIED Schiavo, Giampietro UNSPECIFIED UNSPECIFIED UNSPECIFIED Wishart, Thomas M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Groen, Ewout J. N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gillingwater, Thomas H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-171399
DOI:	10.1093/brain/awy237
Journal or Publication Title:	Brain
Volume:	141
Page Range:	S. 2878 - 2895
Date:	2018
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2156
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TRANSFER-RNA SYNTHETASE; ANTICODON-BINDING DOMAIN; MOUSE MODEL; UBIQUITIN HOMEOSTASIS; RESPIRATORY-DISTRESS; SMN PROTEIN; MUTATIONS; NEURONS; UBA1; SURVIVAL Multiple languages Clinical Neurology; Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17139