Generation of interchangeable disease models for Charcot-Marie-Tooth involving tRNA-synthetases: a search for common druggable pathways. 01/01/2018 - 30/06/2022

Abstract

Charcot-Marie-Tooth disease is an incurable hereditary neurodegenerative disorder characterized by severe and progressive sensori-motor deficits. More than 80 genes have been described to cause this pathology and among them there are 6 aminoacyl tRNA-synthetases (ARS) rendering them a prominent CMT-causing genes family. Interestingly, all the mutations lead to an axonal phenotype. ARS are ubiquitously expressed enzyme involved in the initial step of protein biosynthesis, therefore they are indispensable for cell viability. So far, it still remains mysterious how molecular defects in these proteins could cause neurodegeneration with the same spectrum of neuropathic symptoms. My project is to investigate if there is an existence of a common toxic pathway in mutant ARS associated with CMT. I will employ a unique combination of experimental approaches (cell biology, proteomics, microscopy, Drosophila genetics and behavioral assay) using experiment tools (human neuroblastoma cells and Drosophila fly model) to systematically dissect the ARS proteins network and to identify a common pathogenic pathway involved in CMT. Based on the mechanistic insight, I will provide new model to study CMT and a new concept to alleviate mutant-specific neurodegenerative phenotypes. Ultimately, my findings can be extended to other acquired and inherited neuropathies and will facilitate the development of pharmacological strategies for the treatment of these debilitating disease.

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Project type(s)

  • Research Project