美国斯坦福大学医学院Aaron D. Gitler小组的研究显示，FTD/ALS的TDP-43核缺失引起广泛的选择性多腺苷化改变。该研究于2025年10月21日发表于国际一流学术期刊《自然—神经科学》杂志上。

本研究表明，人类大脑神经元核中TDP-43的缺失和TDP-43的疾病导管突变与选择性多聚腺苷酸化（APA）的广泛变化有关。利用高分辨率的聚腺苷化位点图谱，研究组全面定义了TDP-43在人类干细胞来源的神经元中调节的APA事件，并发现TDP-43结合的强度和位置都会影响聚A位点的图像。由TDP-43缺失引发的APA事件会影响疾病相关基因（如SFPQ、NEFL和TMEM106B）的表达。这些发现提供了证据，除了隐性外显子嵌套外，APA变化是TDP-43病理的一个新方面。

据了解，在额颞叶痴呆和肌萎缩侧索硬化症中，RNA结合蛋白TDP-43从脑和脊髓神经元的核核中消失。在mRNA前剪接过程中，TDP-43的一个关键功能是作为隐外显子内含子的抑制因子，但TDP-43在其他RNA加工事件中的作用尚不清楚。

附：英文原文

Title: TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes

Author: Zeng, Yi, Lovchykova, Anastasiia, Akiyama, Tetsuya, Rayner, Stephanie L., Maheswari Jawahar, Vidhya, Liu, Chang, Sianto, Odilia, Guo, Caiwei, Calliari, Anna, Prudencio, Mercedes, Dickson, Dennis W., Petrucelli, Leonard, Gitler, Aaron D.

Issue&Volume: 2025-10-21

Abstract: In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus of neurons in the brain and spinal cord. A key function of TDP-43 has emerged as a repressor of cryptic exon inclusion during pre-mRNA splicing, but a role for TDP-43 in other RNA-processing events remains unresolved. Here we show that loss of TDP-43 from neuronal nuclei of human brain and disease-causing mutations in TDP-43 are associated with widespread changes in alternative polyadenylation (APA). Using high-resolution polyadenylation site mapping, we comprehensively defined TDP-43-regulated APA events in human stem cell-derived neurons and found that both the strength and position of TDP-43 binding influence polyA site usage. APA events caused by loss of TDP-43 impact expression of disease-relevant genes (for example, SFPQ, NEFL and TMEM106B). These findings provide evidence that, in addition to cryptic exon inclusion, APA changes are a new facet of TDP-43 pathology.

DOI: 10.1038/s41593-025-02049-3

Source: https://www.nature.com/articles/s41593-025-02049-3