Unraveling the signaling mechanisms leading to Dominant Intermediate Charcot-Marie-Tooth type C neuropathy.

Dominant intermediate Charcot-Marie-Tooth disease type C (DI-CMTC) is an incurable hereditary neurodegenerative disorder characterized by severe and progressive sensory-motor deficits. DICMTC is caused by mutations in the tyrosyl-tRNA synthetase (YARS), an essential enzyme involved in the initial steps of protein biosynthesis and therefore indispensable for cell viability. It remains enigmatic how molecular defects in this housekeeper protein could cause degeneration restricted to peripheral nerves. Our goal is to unravel the molecular mechanisms underlying YARS neurotoxicity and to translate these findings into potential pharmacological therapies for DI-CMTC. I will employ a combination of systematic "omics" approaches (proteomics, interactomics, functional genomics) and unique experimental tools (Drosophila and neuroblastoma genetic models) in order to unravel the neuronal signaling response elicited by mutant YARS proteins. The identified key molecular players will be functionally characterized and used to alleviate mutantspecific neurodegenerative phenotypes in the only existing animal model of DI-CMTC (Drosophila melanogaster). Ultimately, my findings can be extended to other inherited or acquired neuropathies and will facilitate the development of pharmacological strategies for the treatment of these debilitating diseases.

Keywords:CHARCOT-MARIE-TOOTH DISEASE

Disciplines:Systems biology