Exploring the role of phosphor-signaling in the etiology of tRNA- synthetase-associated peripheral neuropathies.

Aminoacyl-tRNA synthetases (ARS) are the largest protein family implicated in Charcot-Marie-Tooth disease (CMT), the commonest inherited peripheral neuropathy. We reported that mutations in tyrosyl-tRNA synthetase (YARS) cause Dominant Intermediate CMT type C (DI-CMTC). ARS are ubiquitous enzymes essential for protein biosynthesis. It is unknown which cellular mechanisms are triggered by the mutant enzymes and how this causes neurodegeneration. To gain pathomechanistic insights, we established Drosophila and neuroblastoma models and performed extensive genetic, transcriptomics and biochemical studies. We discovered unique DI-CMTC signatures suggesting that imbalance in phosphor-signaling might underlie the neuropathy. Here, we aim to establish how YARS interacts with phosphor-signaling and to validate our exciting preliminary findings in the most disease-relevant cell model, the patient-derived motoneurons. Next to in-depth mo hological and functional characterization, we will assess their phosphorylation and transcription profiles. We will integrate and match our findings to reconstruct the cellular mechanisms affected by mutant YARS and to pinpoint molecular targets for further manipulation. Finally, we will attempt to pharmacologically reverse the identified disease signatures in the motoneurons to provide a proof of concept for therapy development. Our study will provide mechanistic insights on DI-CMTC and will give tangible clues for designing therapeutic strategies.

Keywords:NEUROPATHIES

Disciplines:Proteins, Cell signalling, Posttranslational modifications, Transcription and translation, Neurological and neuromuscular diseases