The ribonuclear protein TDP-43 has been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS), with genetic mutations being linked to the neurological symptoms of the disease. Though alterations in the intracellular distribution of TDP-43 have been observed in skeletal muscles of patients suffering from ALS, it is not clear whether such modifications play an active role in the disease or merely represent an expression of muscle homeostatic mechanisms. Also, the molecular and metabolic pathways regulated by TDP-43 in the skeletal muscle remain largely unknown. Here, we analyze the function of TBPH, the Drosophila melanogaster ortholog of TDP-43, in skeletal muscles. We modulated the activity of TDP-43 in Drosophila muscles by means of RNA interference and observed that it is required to promote the formation and growth of neuromuscular synapses. TDP-43 regulated the expression levels of Disc-large (Dlg), and restoring Dlg expression either in skeletal muscles or in motoneurons was sufficient to suppress the locomotive and synaptic defects of TDP-43-null flies. These results were validated by the observation of a decrease in Dlg levels in human neuroblastoma cells and iPSC-differentiated motoneurons derived from ALS patients, suggesting similar mechanisms may potentially be involved in the pathophysiology of the disease. Our results help to unveil the physiological role of TDP-43 in skeletal muscles as well as the mechanisms responsible for the autonomous and non-autonomous behavior of this protein concerning the organization of neuromuscular synapses.

中文翻译：

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TDP-43通过调节果蝇骨骼肌中Disc-large表达来促进神经肌肉突触的形成

核糖蛋白TDP-43与肌萎缩性侧索硬化症（ALS）的病理生理有关，其遗传突变与该疾病的神经系统症状有关。尽管已经在患有ALS的患者的骨骼肌中观察到TDP-43的细胞内分布的改变，但是尚不清楚这种修饰在该疾病中是否起积极作用或仅代表肌肉稳态机制的表达。同样，骨骼肌中受TDP-43调节的分子和代谢途径仍然未知。在这里，我们分析了TBPH（TDP-43的果蝇黑腹直系同源基因）在骨骼肌中的功能。我们通过RNA干扰调节了果蝇肌肉中TDP-43的活性，并观察到它需要促进神经肌肉突触的形成和生长。TDP-43调节Disc-large（Dlg）的表达水平，恢复Dlg在骨骼肌或运动神经元中的表达足以抑制TDP-43无效果蝇的机车和突触缺陷。这些结果通过观察到人类神经母细胞瘤细胞和源自ALS患者的iPSC分化的运动神经元中Dlg水平的降低而得到证实，表明该疾病的病理生理可能涉及类似的机制。