Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases
Name
Niehues-2015-Impaired protein.pdf
Size
1.83 MB
Format
Adobe PDF
Checksum (MD5)
88c729e684940d548a565474f32cd522
Author(s)
Niehues, Sven
Bussmann, Julia
Steffes, Georg
Erdmann, Ines
Sun, Litao
Wagner, Marina
Wang, Guangxia
Koerdt, Sophia N.
Stum, Morgane
RajBhandary, Uttam L.
Date Issued
July 2015
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
Niehues, Sven, Julia Bussmann, Georg Steffes, Ines Erdmann, Caroline Kohrer, Litao Sun, Marina Wagner, et al. “Impaired Protein Translation in Drosophila Models for Charcot–Marie–Tooth Neuropathy Caused by Mutant tRNA Synthetases.” Nat Comms 6 (July 3, 2015): 7520. © 2015 Macmillan Publishers Limited
Version
Final published version
Abstract
Dominant mutations in five tRNA synthetases cause Charcot–Marie–Tooth (CMT) neuropathy, suggesting that altered aminoacylation function underlies the disease. However, previous studies showed that loss of aminoacylation activity is not required to cause CMT. Here we present a Drosophila model for CMT with mutations in glycyl-tRNA synthetase (GARS). Expression of three CMT-mutant GARS proteins induces defects in motor performance and motor and sensory neuron morphology, and shortens lifespan. Mutant GARS proteins display normal subcellular localization but markedly reduce global protein synthesis in motor and sensory neurons, or when ubiquitously expressed in adults, as revealed by FUNCAT and BONCAT. Translational slowdown is not attributable to altered tRNA[superscript Gly] aminoacylation, and cannot be rescued by Drosophila Gars overexpression, indicating a gain-of-toxic-function mechanism. Expression of CMT-mutant tyrosyl-tRNA synthetase also impairs translation, suggesting a common pathogenic mechanism. Finally, genetic reduction of translation is sufficient to induce CMT-like phenotypes, indicating a causal contribution of translational slowdown to CMT.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/ncomms8520
