Center for Molecular Neurology, VIB, University of Antwerp, 2610, Antwerpen, Belgium.
Department of Biomedical Sciences, University of Antwerp, 2610, Antwerpen, Belgium.
Nat Commun. 2023 Mar 8;14(1):999. doi: 10.1038/s41467-023-35908-3.
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.
YARS1 及其它六种 tRNA 连接酶的显性突变导致遗传性运动感觉神经病（Charcot-Marie-Tooth peripheral neuropathy，CMT）。它们的致病性并不需要氨酰化作用的丧失，提示存在获得性功能的疾病机制。通过在果蝇中的无偏遗传筛选，我们将 YARS1 功能障碍与肌动蛋白细胞骨架组织联系起来。生化研究揭示了 YARS1 的未知的肌动蛋白成束特性被 CMT 突变增强，导致果蝇神经系统、人 SH-SY5Y 神经母细胞瘤细胞和患者来源的成纤维细胞中的肌动蛋白解聚。F-肌动蛋白组织的遗传调节改善了表达 CMT 致病 YARS1 突变的果蝇神经元的标志性电生理和形态特征。在表达神经病变致病的甘氨酰-tRNA 合成酶的果蝇中也观察到类似的有益效果。因此，在这项工作中，我们表明 YARS1 是一种进化保守的 F-肌动蛋白组织者，它将肌动蛋白细胞骨架与 tRNA 合成酶诱导的神经退行性变联系起来。
