RESUMO
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.
Assuntos
Actinas , Tirosina-tRNA Ligase , Animais , Humanos , Actinas/metabolismo , Doença de Charcot-Marie-Tooth/genética , Drosophila/genética , Glicina-tRNA Ligase/genética , Mutação , RNA de Transferência , Tirosina-tRNA Ligase/genética , Tirosina-tRNA Ligase/metabolismo , Linhagem Celular TumoralRESUMO
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive multisystemic disorder caused by TYMP gene mutations. Here, we report on the first MNGIE patient diagnosed in Bulgaria who carries a novel homozygous TYMP mutation (p.Leu347Pro). The patient presented with gastrointestinal complaints, cachexia, hearing loss, ptosis, ophthalmoparesis, polyneuropathy, cognitive impairment, and leukoencephalopathy on magnetic resonance imaging (MRI) examination of the brain. The patient's motor capacity declined significantly, leading to wheelchair dependence several months following administration of tuberculostatic treatment, suggesting mitochondrial toxicity of these agents. The advanced stage of the disease and the poor medical condition prevented us from performing allogenic hematopoietic stem cell transplantation (HSCT). Early diagnosis is important not only for genetic counseling but also in view of the timely treatment with allogenic HSCT.