Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot-Marie-Tooth neuropathy

Dominant-intermediate Charcot-Marie-Tooth neuropathy (DI-CMT) is characterized by axonal degeneration and demyelination of peripheral motor and sensory neurons. Three dominant mutations in the YARS gene, encoding tyrosyl-tRNA synthetase (TyrRS), have so far been associated with DI-CMT type C. The mo...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 28; pp. 11782 - 11787
Main Authors:	Storkebaum, Erik, Leitão-Gonçalves, Ricardo, Godenschwege, Tanja, Nangle, Leslie, Mejia, Monica, Bosmans, Inge, Ooms, Tinne, Jacobs, An, Van Dijck, Patrick, Yang, Xiang-Lei, Schimmel, Paul, Norga, Koen, Timmerman, Vincent, Callaerts, Patrick, Jordanova, Albena
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 14-07-2009 National Acad Sciences
Subjects:	aminoacyl tRNA ligases animal models Animals Animals, Genetically Modified Biological Sciences Cells Charcot-Marie-Tooth Disease - genetics Charcot-Marie-Tooth Disease - pathology Charcot-Marie-Tooth neuropathy disease models Disease Models, Animal Drosophila Drosophila - enzymology Drosophila - genetics Drosophila - metabolism Drosophila melanogaster Electrophysiology Enzymes genes Genes, Dominant Genetic mutation Genotype & phenotype human diseases Humans Insects Luciferases Motor Activity - genetics Mutation Mutation - genetics nervous system diseases Neurodegenerative diseases Neurons Neurons - metabolism Peripheral nervous system diseases Phenotypes Transfer RNA Transgenes Tyrosine-tRNA Ligase - genetics tyrosyl-tRNA synthetase YARS gene
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Summary:	Dominant-intermediate Charcot-Marie-Tooth neuropathy (DI-CMT) is characterized by axonal degeneration and demyelination of peripheral motor and sensory neurons. Three dominant mutations in the YARS gene, encoding tyrosyl-tRNA synthetase (TyrRS), have so far been associated with DI-CMT type C. The molecular mechanisms through which mutations in YARS lead to peripheral neuropathy are currently unknown, and animal models for DI-CMTC are not yet available. Here, we report the generation of a Drosophila model of DI-CMTC: expression of the 3 mutant--but not wild type--TyrRS in Drosophila recapitulates several hallmarks of the human disease, including a progressive deficit in motor performance, electrophysiological evidence of neuronal dysfunction and morphological signs of axonal degeneration. Not only ubiquitous, but also neuron-specific expression of mutant TyrRS, induces these phenotypes, indicating that the mutant enzyme has cell-autonomous effects in neurons. Furthermore, biochemical and genetic complementation experiments revealed that loss of enzymatic activity is not a common feature of DI-CMTC-associated mutations. Thus, the DI-CMTC phenotype is not due to haploinsufficiency of aminoacylation activity, but most likely to a gain-of-function alteration of the mutant TyrRS or interference with an unknown function of the WT protein. Our results also suggest that the molecular pathways leading to mutant TyrRS-associated neurodegeneration are conserved from flies to humans.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 1E.S., R.L.-G., P.C., and A. Jordanova contributed equally to this work. Author contributions: E.S., R.L.-G., V.T., P.C., and A. Jordanova designed research; E.S., R.L.-G., T.G., L.N., M.M., I.B., T.O., A. Jacobs, and A. Jordanova performed research; T.G., P.V.D., X.-L.Y., and K.N. contributed new reagents/analytic tools; E.S., R.L.-G., T.G., and A. Jordanova analyzed data; and E.S., R.L.-G., P.S., V.T., P.C., and A. Jordanova wrote the paper. Contributed by Paul Schimmel, May 15, 2009
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.0905339106