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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents

ID: 717281.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
Impaired protein translation in Drosophila models for Charcot-Marie-Tooth neuropathy caused by mutant tRNA synthetases
Authors:Niehues, S.; Bussmann, J.; Steffes, G.; Erdmann, I.; Kohrer, C.; Sun, L.; Wagner, M.; Schafer, K.; Wang, G.; Koerdt, S. N.; Stum, M.; RajBhandary, U. L.; Thomas, U.; Aberle, H.; Burgess, R. W.; Yang, X. L.; Dieterich, D.; Storkebaum, E.
Date of Publication (YYYY-MM-DD):2015
Title of Journal:Nat Commun
Start Page:7520
Review Status:Internal review
Audience:Not Specified
Abstract / Description: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(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.
External Publication Status:published
Document Type:Article
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:1] Research Group Neuralomics, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany [2] Institute for Pharmacology and Toxicology, Otto-von-Guericke-University, 39120 Magdeburg, Germany. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. The Scripps Research Institute, La Jolla, California 92037, USA. The Jackson Laboratory, Bar Harbor, Maine 04609, USA. Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany. Functional Cell Morphology Lab, Heinrich Heine University, 40225 Dusseldorf, Germany.
Identifiers:ISSN:2041-1723 (Electronic) 2041-1723 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/26138142 [ID No:2]
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