Ermanoska, B., Asselbergh, B., Morant, L., Petrovic-Erfurth, M.L., Hosseinibarkooie, S., Leitão-Gonçalves, R., Almeida-Souza, L., Bervoets, S., Sun, L., Lee, L., Atkinson, D., Khanghahi, A., Tournev, I., Callaerts, P., Verstreken, P., Yang, X.L., Wirth, B., Rodal, A.A., Timmerman, V., Goode, B.L., Godenschwege, T.A., Jordanova, A. (2023). Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling.  Nat. Commun. 14(1): 999.

FBrf0255977

Research paper

Dominant mutations in tyrosyl-tRNA synthetase (YARS1) and six other tRNA ligases cause Charcot-Marie-Tooth peripheral neuropathy (CMT). Loss of aminoacylation is not required for their pathogenicity, suggesting a gain-of-function disease mechanism. By an unbiased genetic screen in Drosophila, we link YARS1 dysfunction to actin cytoskeleton organization. Biochemical studies uncover yet unknown actin-bundling property of YARS1 to be enhanced by a CMT mutation, leading to actin disorganization in the Drosophila nervous system, human SH-SY5Y neuroblastoma cells, and patient-derived fibroblasts. Genetic modulation of F-actin organization improves hallmark electrophysiological and morphological features in neurons of flies expressing CMT-causing YARS1 mutations. Similar beneficial effects are observed in flies expressing a neuropathy-causing glycyl-tRNA synthetase. Hence, in this work, we show that YARS1 is an evolutionary-conserved F-actin organizer which links the actin cytoskeleton to tRNA-synthetase-induced neurodegeneration.

PMC9995517 (PMC) (EuropePMC)