PDF(Pubmed)
Abstract：
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with a progressive and fatal course. They are often comorbid and share the same molecular spectrum. Their key pathological features are the formation of the aggregation of TDP-43, an RNA-binding protein, in the cytoplasm and its depletion from the nucleus in the central nervous system. In the nucleus, TDP-43 regulates several aspects of RNA metabolism, ranging from RNA transcription and alternative splicing to RNA transport. Suppressing the aberrant splicing events during RNA processing is one of the significant functions of TDP-43. This function is impaired when TDP-43 becomes depleted from the nucleus. Several critical cryptic splicing targets of TDP-43 have recently emerged, such as STMN2, UNC13A, and others. UNC13A is an important ALS/FTD risk gene, and the genetic variations, single nucleotide polymorphisms, cause disease via the increased susceptibility for cryptic exon inclusion under the TDP-43 dysfunction. Moreover, TDP-43 has an autoregulatory mechanism that regulates the splicing of its mRNA (TARDBP mRNA) in the healthy state. This study provides recent findings on the splicing regulatory function of TDP-43 and discusses the prospects of using these aberrant splicing events as efficient biomarkers.
摘要：
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是一种进行性和致命性的神经退行性疾病。它们通常是合并症的，并且共享相同的分子光谱。它们的关键病理特征是TDP-43（一种RNA结合蛋白）的聚集形成，在细胞质中，它从中枢神经系统的细胞核中耗尽。在细胞核中，TDP-43调节RNA代谢的几个方面，从RNA转录和可变剪接到RNA转运。抑制RNA加工过程中的异常剪接事件是TDP-43的重要功能之一。当TDP-43从细胞核耗尽时,该功能受损。最近出现了几个关键的TDP-43的隐秘剪接靶标，如STMN2、UNC13A、和其他人。UNC13A是一个重要的ALS/FTD风险基因,和遗传变异，单核苷酸多态性，在TDP-43功能障碍下，通过增加对隐性外显子包涵体的易感性来引起疾病。此外，TDP-43具有在健康状态下调节其mRNA(TARDBPmRNA)剪接的自动调节机制。这项研究提供了有关TDP-43剪接调节功能的最新发现，并讨论了使用这些异常剪接事件作为有效生物标志物的前景。
