| 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 |
9.412
|
| Times Cited |
62
|
|
WOS Category
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| Resource |
| Drosophila |
4561R-1
4561R-2 |
