Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling.
Biljana ErmanoskaBob AsselberghLaura MorantMaria-Luise Petrovic-ErfurthSeyyedmohsen HosseinibarkooieRicardo Leitão-GonçalvesLeonardo Almeida-SouzaSven BervoetsLitao SunLaTasha LeeDerek AtkinsonAkram KhanghahiIvaylo TournevPatrick CallaertsPatrik VerstrekenXiang-Lei YangBrunhilde WirthAvital Adah RodalVincent TimmermanBruce L GoodeTanja A GodenschwegeAlbena JordanovaPublished in: Nature communications (2023)
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.