Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron loss in the brain and spinal cord; however, its etiology is unknown, and no curative treatment exists. TAR DNA-binding protein 43 (TDP-43), encoded by TARDBP, is a genetic mutation observed in 2–5% of familial ALS, and TDP is known to be mislocalized in the cytoplasm. This study aimed to identify compounds that inhibited the nuclear to cytoplasmic localization of TDP-43 in human induced pluripotent stem (iPS) cells-derived neurons. TDP-43 transgenic human iPS cells were constructed, differentiated into motor neurons, and then treated with MG-132 and sodium arsenite (stressors) to induce nuclear to cytoplasmic localization of TDP-43. STAT3 inhibitors, such as niclosamide, prevented TDP-43 mislocalization and degraded TDP-43 aggregates, and attenuated morphological changes under stress. Furthermore, niclosamide activated mitophagy via the PINK1-parkin-ubiquitin pathway. These findings suggest niclosamide may be a therapeutic candidate for ALS.

肌萎缩侧索硬化 (ALS) 的特点是大脑和脊髓中的运动神经元进行性丧失；然而，其病因不明，也不存在治愈性治疗方法。TAR DNA 结合蛋白 43 (TDP-43)，由TARDBP编码, 是在 2-5% 的家族性 ALS 中观察到的基因突变，已知 TDP 在细胞质中定位错误。本研究旨在鉴定可抑制人诱导多能干 (iPS) 细胞衍生神经元中 TDP-43 细胞核到细胞质定位的化合物。构建 TDP-43 转基因人类 iPS 细胞，分化为运动神经元，然后用 MG-132 和亚砷酸钠（应激物）处理以诱导 TDP-43 的细胞核定位。STAT3 抑制剂，如氯硝柳胺，可防止 TDP-43 错误定位和降解 TDP-43 聚集体，并减轻压力下的形态变化。此外，氯硝柳胺通过 PINK1-parkin-泛素途径激活线粒体自噬。这些发现表明氯硝柳胺可能是 ALS 的治疗候选药物。