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Nat Commun. 2019 Nov 6;10(1):5045. doi: 10.1038/s41467-019-12909-9.

Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy.

Author information

1
Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.
2
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
3
Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str, bl. 21, 1113, Sofia, Bulgaria.
4
Rosenstiel Basic Medical Sciences Research Center, Department of Biology, Brandeis University, Waltham, MA, 02453, USA.
5
VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.
6
Department of Biological Sciences, Florida Atlantic University, 5353 Parkside Drive, Jupiter, FL, 33458, USA.
7
Hereditary Neuropathy Foundation Center of Excellence, Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University, Hackensack University Medical Center, 360 Essex street #303, Hackensack, NJ, 07601, USA.
8
Clinic of Neurology, University Hospital Sofiamed, Sofia University St. Kliment Ohridski, bul. G. M. Dimitrov 16, 1797, Sofia, Bulgaria.
9
Clinic of Neurological Diseases, UMBAL Aleksandrovska, Department of Neurology, Medical University-Sofia, ul. Sveti Georgi Sofiyski 1, 1431, Sofia, Bulgaria.
10
Department of Cognitive Science and Psychology, New Bulgarian University, ul. Montevideo 21, 1618, Sofia, Bulgaria.
11
Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium. albena.jordanova@uantwerpen.vib.be.
12
Department of Medical Chemistry and Biochemistry, Medical University-Sofia, ul. Zdrave 2, 1431, Sofia, Bulgaria. albena.jordanova@uantwerpen.vib.be.
13
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA. xlyang@scripps.edu.

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.

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