DI-CMTC:Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in D

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Proc Natl Acad Sci U S A. 2009 Jun 26.

Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in

Drosophila features of human Charcot-Marie-Tooth

neuropathy.

Storkebaum E, Leitão-Gonçalves R, Godenschwege T, Nangle L, Mejia M, Bosmans I,

Ooms T, s A, Van Dijck P, Yang XL, Schimmel P, Norga K, Timmerman V,

Callaerts P, Jordanova A.

Laboratory of Developmental Genetics.

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.