Department of Stem Cell and Regenerative Biology, Department of Molecular and Cellular Biology, and Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Stem Cell and Regenerative Biology, Department of Molecular and Cellular Biology, and Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, 1081 HV, The Netherlands.
Trends Neurosci. 2021 Jun;44(6):424-440. doi: 10.1016/j.tins.2021.02.008. Epub 2021 Apr 5.
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.
转录反应 DNA 结合蛋白 43kDa（TDP-43）是一种多功能核酸结合蛋白，是与几种毁灭性神经系统疾病相关的不溶性聚集物的主要成分；其编码基因 TARDBP 的突变是家族性肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的病因。在这里，我们回顾了 TDP-43 的既定和新兴作用，并考虑了其功能障碍如何影响神经系统中的 RNA 动态平衡，从而导致神经变性。值得注意的是，最近发现轴突生长相关因子 STMN2 的剪接异常与 TDP-43 功能障碍有关，为 TDP-43 蛋白病和神经病变之间提供了一种机制联系。本综述强调了深入了解 TDP-43 在大脑中的功能如何为几种神经疾病开发新的靶向治疗方法提供了契机。
