Exploring the tissue-specific disease mechanisms underlying 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 that 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 unessential for CMT. It is unknown how this ubiquitous protein leads to a disease manifesting in a length-dependent manner and affecting the peripheral neurons (PNs) only. Our lab found 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 and novel spatial profiling technology, we will investigate how whole transcriptome and specific protein profiles are spatially organized within the PNs and how these differ from non-neuronal tissues within the same patient, or controls. We will also explore where and how much the phosphor-signaling axis is dysregulated. Processing and multimodal integration of RNA and protein datasets will guide selection of differentially regulated key genes to be evaluated genetically and pharmacologically for their therapeutic potential in a YARS-CMT fly model. We will also explore if the YARS pathomechanism is shared with other ARS, broadening the impact of our findings and facilitating the development of drugs for a greater number of patients.

Keywords:NEUROPATHY, NEUROPATHIES, NEURO MUSCULAR DISEASES

Disciplines:Bioinformatics data integration and network biology, Transcription and translation, Neurological and neuromuscular diseases, Neurosciences not elsewhere classified

Project type:Collaboration project