RRC ID 11099
Author Storkebaum E, Leitão-Gonçalves R, Godenschwege T, Nangle L, Mejia M, Bosmans I, Ooms T, Jacobs A, Van Dijck P, Yang XL, Schimmel P, Norga K, Timmerman V, Callaerts P, Jordanova A.
Title Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot-Marie-Tooth neuropathy.
Journal Proc. Natl. Acad. Sci. U.S.A.
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.
Volume 106(28)
Pages 11782-7
Published 2009-7-14
DOI 10.1073/pnas.0905339106
PII 0905339106
PMID 19561293
PMC PMC2702257
MeSH Animals Animals, Genetically Modified Charcot-Marie-Tooth Disease / genetics* Charcot-Marie-Tooth Disease / pathology Disease Models, Animal* Drosophila / enzymology* Drosophila / genetics Drosophila / metabolism Electrophysiology Genes, Dominant Luciferases Motor Activity / genetics Mutation / genetics* Neurons / metabolism Tyrosine-tRNA Ligase / genetics*
IF 9.504
Times Cited 45
Drosophila 4561R-1 4561R-2