Rothstein Jeffrey D, Keeley Olivia, Warlick Caroline, Miller Timothy M, Ly Cindy V, Glass Jonathan D, Coyne Alyssa N
Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nat Commun. 2025 Aug 2;16(1):7092. doi: 10.1038/s41467-025-62482-7.
Nuclear loss and cytoplasmic buildup of the RNA-binding protein TDP-43 is a hallmark of ALS and related disorders. While studies using artificial TDP-43 depletion in neurons have revealed changes in gene expression and splicing, their relevance to actual patients remained unclear. Induced pluripotent stem cell (iPSC)-derived neurons (iPSNs) from 180 individuals, including controls, C9orf72 ALS/FTD, and sporadic ALS (sALS) patients were used to generate and analyze ~32,500 qRT-PCR data points across 20 genes which identified variable, time-dependent signatures of TDP-43 loss of function in individual lines. Notably, the same changes were also seen in postmortem brain tissue from the same patients, confirming that iPSNs accurately model disease. Inducing damage to the nuclear pore complex, specifically by reducing the nucleoporin POM121 in healthy iPSNs, was enough to replicate the molecular changes associated with ALS/FTD TDP-43 dysfunction. This directly links nuclear pore integrity to TDP-43-related pathology. Encouragingly, repairing nuclear pore injury in sALS iPSNs restored normal gene processing disrupted by TDP-43 loss. This study (1) provides a valuable population-scale resource for studying TDP-43 dysfunction in ALS, (2) confirms that patient-derived iPSNs closely reflect disease processes seen in the brain, and (3) demonstrates that targeting nuclear pore injury may offer a promising therapeutic strategy in ALS.
RNA结合蛋白TDP-43的核内缺失和胞质聚集是肌萎缩侧索硬化症(ALS)及相关疾病的一个标志。虽然在神经元中使用人工诱导TDP-43缺失的研究揭示了基因表达和剪接的变化,但其与实际患者的相关性仍不明确。研究人员利用来自180名个体(包括对照、C9orf72型ALS/额颞叶痴呆(FTD)和散发性ALS(sALS)患者)的诱导多能干细胞(iPSC)衍生神经元(iPSN),生成并分析了20个基因的约32,500个定量逆转录聚合酶链反应(qRT-PCR)数据点,确定了各个细胞系中TDP-43功能丧失的可变的、时间依赖性特征。值得注意的是,在同一患者的死后脑组织中也观察到了相同的变化,证实了iPSN能够准确模拟疾病。在健康的iPSN中特异性地减少核孔蛋白POM121,从而诱导对核孔复合体的损伤,足以复制与ALS/FTD TDP-43功能障碍相关的分子变化。这直接将核孔完整性与TDP-43相关病理学联系起来。令人鼓舞的是,修复sALS iPSN中的核孔损伤可恢复因TDP-43缺失而破坏的正常基因加工过程。本研究(1)为研究ALS中TDP-43功能障碍提供了宝贵的群体规模资源,(2)证实了患者来源的iPSN密切反映了大脑中所见的疾病过程,(3)表明针对核孔损伤可能为ALS提供一种有前景的治疗策略。