Title: Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot-Marie-Tooth neuropathy
Authors: Storkebaum, Erik ×
Leitao-Goncalves, Ricardo
Godenschwege, Tanja
Nangle, Leslie
Mejia, Monica
Bosmans, Inge
Ooms, Tinne
Jacobs, An
Van Dijck, Patrick
Yang, Xiang-Lei
Schimmel, Paul
Norga, Koenraad
Timmerman, Vincent
Callaerts, Patrick
Jordanova, Albena #
Issue Date: Jul-2009
Publisher: Natl acad sciences
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:106 issue:28 pages:11782-11787
Abstract: 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.
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Microbiology and Biotechnology Section - miscellaneous (-)
Laboratory of Behavioral and Developmental Genetics
Pediatric Hematology & Oncology Section (-)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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