The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
Nat Commun. 2023 Apr 20;14(1):2176. doi: 10.1038/s41467-023-37630-6.
Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts. Here, we present a comprehensive compendium of 429 iPSMNs from 15 datasets, and 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, we identify robust upregulation of p53 signalling in ALS in both iPSMNs and post-mortem spinal cord. p53 activation is greatest with C9orf72 repeat expansions but is weakest with SOD1 and FUS mutations. TDP-43 depletion potentiates p53 activation in both post-mortem neuronal nuclei and cell culture, thereby functionally linking p53 activation with TDP-43 depletion. ALS iPSMNs and post-mortem tissue display enrichment of splicing alterations, somatic mutations, and gene fusions, possibly contributing to the DNA damage response.
肌萎缩性侧索硬化症（ALS）导致运动神经元变性，97%的病例表现出 TDP-43 蛋白病。由于疾病异质性和获取运动神经元的困难，阐明发病机制受到了阻碍。人类诱导多能干细胞衍生的运动神经元（iPSMNs）提供了一种解决方案；然而，这些研究通常受到样本量小的限制。在这里，我们展示了来自 15 个数据集的 429 个人 iPSMNs 和 271 个死后脊髓样本的综合汇编。使用可重复的生物信息学工作流程，我们在 iPSMNs 和死后脊髓中都发现了 ALS 中 p53 信号的显著上调。C9orf72 重复扩展导致 p53 激活最强，但 SOD1 和 FUS 突变导致 p53 激活最弱。TDP-43 耗竭在死后神经元核和细胞培养中均增强了 p53 的激活，从而将 p53 激活与 TDP-43 耗竭在功能上联系起来。ALS iPSMNs 和死后组织显示剪接改变、体细胞突变和基因融合的富集，可能有助于 DNA 损伤反应。
