un13a剪接纠正可修复TDP-43缺失引起的突触功能障碍，这一成果由伦敦大学学院Fratta, Pietro研究小组经过不懈努力而取得。相关论文于2026年11月11日发表在《自然》杂志上。

在这里，研究组发现TDP-43的缺失诱导了一种退行性状态，在这种状态下，神经元结构保持完整，但突触通讯受到严重破坏。对UNC13A中单个隐剪接事件的遗传校正足以挽救这些缺陷。研究组开发了剪接开关反义寡核苷酸，纠正了人类皮质和脊髓运动神经元以及人源化motheme模型中UNC13A的隐剪接。在人类神经元中，这种干预恢复了自发活动，并诱发了突触囊泡释放、单个突触释放概率和更广泛的网络同步。总之，这建立了UNC13A剪接校正作为一种机制定义和基因验证的治疗策略，与大约97%的肌萎缩性侧索硬化症患者和大约50%的TDP-43病理额颞叶痴呆患者相关。

据了解，TDP-43核缺失是肌萎缩性侧索硬化症和额颞叶痴呆的一个典型病理特征，它在数百个转录中诱发广泛的隐式剪接缺陷。尽管如此，TDP-43缺失是否影响突触功能仍不清楚。

附：英文原文

Title: UNC13A splice correction rescues synaptic dysfunction induced by TDP-43 loss

Author: Keuss, Matthew J., Harley, Peter, Ryadnov, Eugeni, Jackson, Rachel E., Boll, Moritz, Zanovello, Matteo, Wilkins, Oscar G., Barattucci, Simone, Ilic, Dragana, Simkin, Rebecca L., Chien, Max Z. Y. J., Cammack, Alexander J., olti, Darija, Mehta, Puja R., Ling, Yan To, Kowald, Maria, Morrie, Ryan D., Miller, Georgiana, Oliveira, Marcio G., Duddy, Graham, Wood, Sophie, Parkes, Joanna E., Sinha, Aparna, Correa-Snchez, Andrs F., Isaacs, Adrian M., Oliver, Peter L., Hamid, Fursham, Green, Eric M., Fisher, Elizabeth M. C., Davies, Benjamin, Schiavo, Giampietro, Shah, Mala, Lipstein, Noa, Burrone, Juan, Fratta, Pietro

Issue&Volume: 2026-11-11

Abstract: TDP-43 nuclear depletion is a defining pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia that induces widespread cryptic splicing defects in hundreds of transcripts1,2,3,4,5,6,7,8. Despite this, whether TDP-43 loss affects synaptic function has remained unclear. Here we show that TDP-43 loss induces a predegenerative state in which neurons remain structurally intact but suffer a substantial breakdown in synaptic communication. Genetic correction of a single cryptic splicing event in UNC13A was sufficient to rescue these deficits. We developed splice-switching antisense oligonucleotides that correct UNC13A cryptic splicing in human cortical and spinal motor neurons and in a humanized mouse model. In human neurons this intervention restored spontaneous and evoked synaptic vesicle release, release probability at individual synapses and wider network synchrony. Together, this establishes UNC13A splice correction as a mechanistically defined and genetically validated therapeutic strategy relevant to roughly 97% of patients with amyotrophic lateral sclerosis and roughly 50% of patients with frontotemporal dementia with TDP-43 pathology.

DOI: 10.1038/s41586-026-11256-2

Source: https://www.nature.com/articles/s41586-026-11256-2

期刊信息

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504

官方网址：http://www.nature.com/

投稿链接：http://www.nature.com/authors/submit_manuscript.html