Abstract
Aminoacyl-tRNA synthetases (ARS) are the largest protein family implicated in Charcot-Marie-Tooth disease (CMT), the commonest inherited peripheral neuropathy. CMT is currently incurable. Our lab reported that mutations in tyrosyl-tRNA synthetase (YARS) cause CMT. YARS catalyzes a critical step in translation, but loss of this function is not required for CMT occurrence. It remains unknown how dysregulation of such ubiquitous protein leads to a disease manifesting in a length-dependent manner and affecting the peripheral neurons (PNs) only. Our lab demonstrated presence of YARS in different neuronal compartments, where it likely executes various functions. Moreover, YARS mutations induce transcriptome and phosphorylation changes in invertebrate and vertebrate models. Using unique patient biosamples, I will investigate how whole transcriptome and specific protein profiles are spatially organized within the PNs and how these differ compared to muscle tissue. I will also explore where and how much the phosphorsignaling axis is dysregulated. Bioinformatics integration of RNA and protein datasets will guide selection of differentially regulated key molecules to be evaluated genetically and pharmacologically for their therapeutic potential in a YARS-CMT fly model. I will also explore if the YARS pathomechanism is shared with other CMT-causing ARS, broadening the impact of my findings and facilitating the development of drugs for a greater number of patients.
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