論文 - 詳細
| RRC ID | 11099 |
|---|---|
| 著者 | 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. |
| タイトル | Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot-Marie-Tooth neuropathy. |
| ジャーナル | 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. |
| 巻・号 | 106(28) |
| ページ | 11782-7 |
| 公開日 | 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 | 9.412 |
| 引用数 | 62 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 15 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ショウジョウバエ | 4561R-1 4561R-2 |