Unraveling the nuclear function of mutant tyrosyl-tRNA synthetase and the link with dominant intermediate Charcot-Marie-Tooth disease type C.

Aminoacyl-tRNA synthetases are essential enzymes, governing the precise translation of genetic information into proteins. Mutations in four 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 as a functional platform 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. Supported by exciting preliminary data, we will combine different "omics" approaches to identify regulatory networks and pathways of neurotoxicity triggered by the DI-CMTC mutations in the nucleus. 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.

Keywords:AMINOACYL-TRNA SYNTHETASES, DROSOPHILA MELANOGASTER, NUCLEUS

Disciplines:Genetics, Systems biology, Molecular and cell biology, Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing