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

Year: 2019
Type: article
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.
DOI: 10.1038/s41467-019-12909-9
Authors: 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, Xiang-Lei Yang
Institutions: University of Antwerp, VIB-UAntwerp Center for Molecular Neurology, Scripps Research Institute, Bulgarian Academy of Sciences, Institute of Molecular Biology, Brandeis University, Florida Atlantic University, Seton Hall University, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Sofia University "St. Kliment Ohridski", New Bulgarian University, Alexandrovska Hospital, Medical University of Sofia
Language: English
Open Access status: gold
Estimated APC paid: $5,200
Funders: Florida Atlantic University, Universidad del Atlántico, Fonds Wetenschappelijk Onderzoek, Universiteit Antwerpen, Vlaamse regering, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Elucidating pathological mechanism of DI-CMTC, Unraveling the nuclear function of tyrosyl-tRNA synthetase and its connection to Dominant Intermediate Charcot-Marie -Tooth type C disease., G2165458014, G24252334, Nuclear function of L1-type CAMs in the drosophila nervous system, Extra-translational roles of aminoacyl tRNA synthetases in connection to disease
OpenAlex ID: W2988098281
FWCI: 2.029
Cites: 55
Cited by: 39
Related to: 10