Transactive response DNA binding protein 43 (TDP-43) is an RNA processing protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Nuclear TDP-43 mislocalizes in patients to the cytoplasm, where it forms ubiquitin-positive inclusions in affected neurons and glia. Physiologically, cytoplasmic TDP-43 is associated with stress granules (SGs). Here, we explored TDP-43 cytoplasmic accumulation and stress granule formation following osmotic and oxidative stress. We show that sorbitol drives TDP-43 redistribution to the cytoplasm, while arsenite induces the recruitment of cytoplasmic TDP-43 to TIA-1 positive SGs. We demonstrate that inducing acute oxidative stress after TDP-43 cytoplasmic relocalization by osmotic shock induces poly (ADP-ribose) polymerase (PARP) cleavage, which triggers cellular toxicity. Recruitment of cytoplasmic TDP-43 to polyribosomes occurs in an SH-SY5Y cellular stress model and is observed in FTD brain lysate. Moreover, the processing body (P-body) marker DCP1a is detected in TDP-43 granules during recovery from stress. Overall, this study supports a central role for cytoplasmic TDP-43 in controlling protein translation in stressed cells.

中文翻译：

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细胞质 TDP-43 参与应激恢复过程中的细胞命运

反式反应 DNA 结合蛋白 43 (TDP-43) 是一种 RNA 加工蛋白，对肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的发病机制至关重要。核 TDP-43 在患者中错误定位于细胞质，在受影响的神经元和神经胶质中形成泛素阳性包涵体。生理学上，细胞质 TDP-43 与应激颗粒 (SG) 相关。在这里，我们探讨了渗透和氧化应激后 TDP-43 细胞质积累和应激颗粒形成。我们显示山梨糖醇驱动 TDP-43 重新分布到细胞质，而亚砷酸盐诱导细胞质 TDP-43 募集到 TIA-1 阳性 SG。我们证明通过渗透休克诱导 TDP-43 细胞质重新定位后的急性氧化应激诱导聚（ADP-核糖）聚合酶（PARP）切割，这会触发细胞毒性。细胞质 TDP-43 募集到多核糖体发生在 SH-SY5Y 细胞应激模型中，并在 FTD 脑裂解物中观察到。此外，在从压力中恢复期间，在 TDP-43 颗粒中检测到处理体 (P-body) 标记 DCP1a。总体而言，这项研究支持细胞质 TDP-43 在控制应激细胞中的蛋白质翻译中的核心作用。