期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-12909-9
关键词
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资金
- US National Institutes of Health [R01-NS085092, R01-GM088278]
- US National Institute for Neurological Disease and Stroke [R15NS090043]
- Research Fund of the University of Antwerp [TOP-BOF-29069]
- Fund for Scientific Research-Flanders (FWO) [G078414N]
- AFM-Telethon, France [16197]
- Fund for Scientific Research-Flanders
- National Foundation for Cancer Research
- Jupiter Life Sciences Initiative of Florida Atlantic University
- DdT2 fellowship from the AFM-Telethon, France
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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