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
|
リソース情報 |
ショウジョウバエ |
4561R-1
4561R-2 |