Gladstone Institute of Neurological Disease, University of California, San Francisco 94158, USA.
Rev Neurosci. 2010;21(4):251-72. doi: 10.1515/revneuro.2010.21.4.251.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are late-onset neurodegenerative disorders that are associated with mutations in the TARDBP gene. The product of this gene, TDP-43, has also been identified as the main component of the intracellular inclusions typical of most cases of ALS and FTD. Recent evidence suggests that TDP-43 is essential for proper development and involved in several fundamental cellular processes, including gene transcription, RNA processing, and the spatial regulation of mRNA translation. Pathogenic TARDBP mutations that impair TDP-43 function could therefore be related to neuronal degeneration in ALS and FTD. Conversely, cellular and animal studies have shown that pathogenic TARDBP mutations induce neuronal toxicity through mislocalization or elevated concentrations of TDP-43, consistent with a gain-of-function mechanism. In this review, we focus on the physiologic functions of TDP-43 within the central nervous system and discuss how these functions may be perturbed or pathologically altered by disease-associated mutations.
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是两种迟发性神经退行性疾病，与 TARDBP 基因突变有关。该基因的产物 TDP-43 也被确定为大多数 ALS 和 FTD 病例中细胞内包涵体的主要成分。最近的证据表明，TDP-43 对于正常发育是必需的，并且参与了几个基本的细胞过程，包括基因转录、RNA 处理和 mRNA 翻译的空间调节。因此，破坏 TDP-43 功能的致病性 TARDBP 突变可能与 ALS 和 FTD 中的神经元退化有关。相反，细胞和动物研究表明，致病性 TARDBP 突变通过 TDP-43 的位置异常或浓度升高诱导神经元毒性，符合功能获得机制。在这篇综述中，我们重点讨论了 TDP-43 在中枢神经系统中的生理功能，并讨论了疾病相关突变如何干扰或病理性改变这些功能。
