Abstract

Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic strategy for CMT.

Details

Title
Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy
Author
Bervoets, Sven 1   VIAFID ORCID Logo  ; Na, Wei 2 ; Maria-Luise Erfurth 1 ; Yusein-Myashkova, Shazie 3 ; Ermanoska, Biljana 4 ; Mateiu, Ligia 5 ; Asselbergh, Bob 5 ; Blocquel, David 2 ; Kakad, Priyanka 6 ; Penserga, Tyrone 6 ; Thomas, Florian P 7 ; Guergueltcheva, Velina 8 ; Tournev, Ivailo 9 ; Godenschwege, Tanja 6   VIAFID ORCID Logo  ; Jordanova, Albena 10   VIAFID ORCID Logo  ; Xiang-Lei, Yang 2   VIAFID ORCID Logo 

1  Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerpen, Belgium 
2  Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA 
3  Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerpen, Belgium; Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria 
4  Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerpen, Belgium; Rosenstiel Basic Medical Sciences Research Center, Department of Biology, Brandeis University, Waltham, MA, USA 
5  VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerpen, Belgium 
6  Department of Biological Sciences, Florida Atlantic University, Jupiter, FL, USA 
7  Hereditary Neuropathy Foundation Center of Excellence, Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University, Hackensack University Medical Center, Hackensack, NJ, USA 
8  Clinic of Neurology, University Hospital Sofiamed, Sofia University St. Kliment Ohridski, Sofia, Bulgaria 
9  Clinic of Neurological Diseases, UMBAL Aleksandrovska, Department of Neurology, Medical University-Sofia, Sofia, Bulgaria; Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria 
10  Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerpen, Belgium; Department of Medical Chemistry and Biochemistry, Medical University-Sofia, Sofia, Bulgaria 
Pages
1-14
Publication year
2019
Publication date
Nov 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-12909-9
ProQuest document ID
2312547280
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.