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Title
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Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in **Drosophila** features of human CharcotMarieTooth neuropathy
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Author
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Abstract
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| Dominant-intermediate CharcotMarieTooth 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 mutantbut not wild typeTyrRS 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. |
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Language
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English
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Source (journal)
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Proceedings of the National Academy of Sciences of the United States of America. - Washington, D.C.
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Publication
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Washington, D.C.
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2009
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ISSN
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0027-8424
[Print]
1091-6490
[Online]
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DOI
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10.1073/PNAS.0905339106
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Volume/pages
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106
:28
(2009)
, p. 11782-11787
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ISI
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000267972700065
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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