TDP-43缺失在ALS/FTD中诱导隐性聚腺苷化，这一成果由伦敦大学学院Pietro Fratta小组经过不懈努力而取得。相关论文于2025年10月21日发表在《自然—神经科学》杂志上。

在这项研究中，该课题组研究人员开发了一个生物信息学管道，以可靠地识别替代的最后外显子，3'非翻译区（3' utr）延伸和内含子多腺苷化APA事件类型，该课题组研究人员鉴定了诱导多能干细胞（iPSC）来源的神经元中由TDP-43缺失诱导的隐性APA位点。TDP-43的结合位点在这些隐事件的位点富集，TDP-43可以抑制和增强APA。在ALS和额颞叶痴呆（FTD）死后脑组织中也发现了所有类别的隐性APA。RNA测序（RNA-seq）、巯基（SH）烷基化RNA代谢测序（SLAM-seq）和核糖体分析（核糖-seq）显示，不同的隐式APA类别对转录物水平有不同的下游影响，隐式3'UTR延伸可以增加RNA的稳定性，从而增加翻译量。总之，研究小组证明了TDP-43核耗竭诱导隐性APA，扩大了TDP-43已知后果的范围。

据了解，核耗竭和RNA结合蛋白TDP-43的细胞质聚集是肌萎缩性侧索硬化症（ALS）的细胞特征。TDP-43核缺失与隐性外显子的去抑制有关，但隐性选择性聚腺苷酸化（APA）事件在很大程度上被忽视了。

附：英文原文

Title: TDP-43 loss induces cryptic polyadenylation in ALS/FTD

Author: Bryce-Smith, Sam, Brown, Anna-Leigh, Chien, Max Z. Y. J., Dattilo, Dario, Mehta, Puja R., Mattedi, Francesca, Barattucci, Simone, Mikheenko, Alla, Zanovello, Matteo, Pellegrini, Flaminia, El-Agamy, Sara Emad, Yome, Matthew, Hill, Sarah E., Qi, Yue A., Sun, Kai, Ryadnov, Eugeni, Wan, Yixuan, Vargas, Jose Norberto S., Birsa, Nicol, Raj, Towfique, Humphrey, Jack, Keuss, Matthew, Wilkins, Oscar G., Ward, Michael, Secrier, Maria, Fratta, Pietro

Issue&Volume: 2025-10-21

Abstract: Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 are cellular hallmarks of amyotrophic lateral sclerosis (ALS). TDP-43 nuclear loss causes de-repression of cryptic exons, yet cryptic alternative polyadenylation (APA) events have been largely overlooked. In this study, we developed a bioinformatic pipeline to reliably identify alternative last exons, 3’ untranslated region (3’UTR) extensions and intronic polyadenylation APA event types, and we identified cryptic APA sites induced by TDP-43 loss in induced pluripotent stem cell (iPSC)-derived neurons. TDP-43 binding sites are enriched at sites of these cryptic events, and TDP-43 can both repress and enhance APA. All categories of cryptic APA were also identified in ALS and frontotemporal dementia (FTD) postmortem brain tissue. RNA sequencing (RNA-seq), thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) and ribosome profiling (Ribo-seq) revealed that distinct cryptic APA categories have different downstream effects on transcript levels and that cryptic 3’UTR extensions can increase RNA stability, leading to increased translation. In summary, we demonstrate that TDP-43 nuclear depletion induces cryptic APA, expanding the palette of known consequences of TDP-43.

DOI: 10.1038/s41593-025-02050-w

Source: https://www.nature.com/articles/s41593-025-02050-w