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Project

Characterization of a novel pathomechanism causing Charcot-Marie-Tooth disease and its therapeutic targeting.

Aminoacyl-tRNA synthetases are essential enzymes, governing the precise translation of genetic information into proteins. Mutations in six of them lead to different subtypes of Charcot-Marie-Tooth disease (CMT), the most common inherited peripheral neuropathy. We established that Dominant Intermediate CMT type C (DI-CMTC) is caused by genetic defects in tyrosyl-tRNA synthetase (YARS). It is challenging to understand how mutations in this primordial enzyme lead to a specific neuronal degeneration. To gain insights in disease pathology, we developed a Drosophila DI-CMTC model, which successfully recapitulated several hallmarks of CMT pathophysiology. Here, we will use this model to validate the hypothesis that neuronal toxicity of YARS is exerted in the nucleus, where DI-CMTC mutations interfere with an ex-translational function of this protein. We will combine different "omics" approaches to identify regulatory networks and pathways of neurotoxicity triggered by the DI-CMTC mutations in the nucleus. Subsequently, the effect of their therapeutic targeting will be evaluated in an in vivo chemical genetic screen in Drosophila. In this way, we will use our fly DI-CMTC model not only as a genetic tool to unravel disease mechanisms, but also as a preclinical platform for CMT drug discovery. Our findings will contribute to a better understanding of the fundamental role of tRNA synthetases in organismal biology, will provide mechanistic insights on the neurodegenerative process associated with DI-CMTC and other disorders with common etiology, and will open avenues for the development of novel treatment strategies for CMT patients.
Date:1 Dec 2014 →  30 Nov 2018
Keywords:GENOTYPE-PHENOTYPE CORRELATION, GENE IDENTIFICATION, GENETIC DISEASE, GENETIC SCREENING
Disciplines:Genetics, Systems biology, Molecular and cell biology, Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing