Transactive response DNA-binding protein 43 kDa (TDP-43), a multifunctional nucleic acid-binding protein, is a primary component of insoluble aggregates associated with several devastating nervous system disorders; mutations in TARDBP, its encoding gene, are a cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we review established and emerging roles of TDP-43 and consider how its dysfunction impinges on RNA homeostasis in the nervous system, thereby contributing to neural degeneration. Notably, improper splicing of the axonal growth-associated factor STMN2 has recently been connected to TDP-43 dysfunction, providing a mechanistic link between TDP-43 proteinopathies and neuropathy. This review highlights how a deep understanding of the function of TDP-43 in the brain might be leveraged to develop new targeted therapies for several neurological disorders.

反式反应 DNA 结合蛋白 43 kDa (TDP-43) 是一种多功能核酸结合蛋白，是与几种破坏性神经系统疾病相关的不溶性聚集体的主要成分；TARDBP突变其编码基因是家族性肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的原因。在这里，我们回顾了 TDP-43 的既定和新兴角色，并考虑其功能障碍如何影响神经系统中的 RNA 稳态，从而导致神经退化。值得注意的是，轴突生长相关因子 STMN2 的不当剪接最近与 TDP-43 功能障碍有关，提供了 TDP-43 蛋白病和神经病之间的机制联系。这篇综述强调了如何利用对 TDP-43 在大脑中功能的深刻理解来开发针对几种神经系统疾病的新靶向疗法。