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

Sven Bervoets, Na Wei, Maria-Luise Erfurth, Shazie Yusein-Myashkova, Biljana Ermanoska, Ligia Mateiu, Bob Asselbergh, David Blocquel, Priyanka Kakad, Tyrone Penserga, Florian P Thomas, Velina Guergueltcheva, Ivailo Tournev, Tanja Godenschwege, Albena Jordanova () and Xiang-Lei Yang ()
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Sven Bervoets: University of Antwerp
Na Wei: The Scripps Research Institute
Maria-Luise Erfurth: University of Antwerp
Shazie Yusein-Myashkova: University of Antwerp
Biljana Ermanoska: University of Antwerp
Ligia Mateiu: University of Antwerp
Bob Asselbergh: University of Antwerp
David Blocquel: The Scripps Research Institute
Priyanka Kakad: Florida Atlantic University
Tyrone Penserga: Florida Atlantic University
Florian P Thomas: Hackensack University Medical Center
Velina Guergueltcheva: University Hospital Sofiamed, Sofia University St. Kliment Ohridski
Ivailo Tournev: Medical University-Sofia
Tanja Godenschwege: Florida Atlantic University
Albena Jordanova: University of Antwerp
Xiang-Lei Yang: The Scripps Research Institute

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12909-9

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