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Project

Establishment, characterization and phosphor-profiling of the first iPSC model for aminoacyl-tRNA synthetase induced peripheral neuropathies.

Aminoacyl-tRNA synthetases (ARS) are the largest family of proteins implicated in Charcot-Marie- Tooth disease (CMT), the most common inherited peripheral neuropathy. CMT is a life-long and incurable disease. ARS are ubiquitous essential enzymes normally required for protein biosynthesis. However, in neurodegeneration, a distinct unknown cellular mechanism triggered by the CMT mutations in ARS is at play. We have established Drosophila and cellular CMT models and studied the pathways altered in presence of mutations in tyrosyl-tRNA synthetase (YARS). By utilizing these models in a complimentary manner, we have solid evidence that dysregulated phosphor-signaling might underlie ARS-related CMT. Here, I propose to translate these exciting findings from flies and neuroblastoma cells to human motorneurons (MNs), the primary cell type affected by the CMT-ARS mutations. I will establish iPSC derived MNs from YARS-CMT patients and will assess spatially and quantitatively their phosphorylation profile. Then I will attempt to pharmacologically revert the disease profile signatures to healthy state. Thereby, I will not only provide a proof of concept for future CMT therapies, but will also characterize a novel role of the YARS protein in phosphor-signaling.
Date:1 Oct 2019 →  30 Sep 2023
Keywords:CHARCOT-MARIE-TOOTH DISEASE, PERIPHERAL NEUROPATHIES
Disciplines:Cell signalling, Genetics, Posttranslational modifications, Transcription and translation, Neurological and neuromuscular diseases