Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Centre de Recherches en Biomédecine, Strasbourg, France.
Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University, Nijmegen, Netherlands.
Nat Commun. 2023 Jan 20;14(1):342. doi: 10.1038/s41467-022-35724-1.
Amyotrophic lateral sclerosis (ALS) has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA-binding proteins including TDP-43 and FUS. A transcriptome wide association study (TWAS) identified 6 loci associated with ALS, including in NUP50 encoding for the nucleopore basket protein NUP50. Independently, rare variants in NUP50 were associated with ALS risk (P = 3.71.10; odds ratio = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying a NUP50 frameshift mutation displayed a decreased level of NUP50. Loss of NUP50 leads to death of cultured neurons, and motor defects in Drosophila and zebrafish. Thus, our study identifies alterations in splicing in neurons as critical in ALS and provides genetic evidence linking nuclear pore defects to ALS.
肌萎缩侧索硬化症（ALS）具有显著的遗传性，部分与额颞叶痴呆（FTD）共享。我们表明，ALS 的遗传性在剪接变体和 6 种 RNA 结合蛋白（包括 TDP-43 和 FUS）的结合位点中富集。全转录组关联研究（TWAS）确定了与 ALS 相关的 6 个位点，包括编码核孔篮蛋白 NUP50 的 NUP50 基因。此外，在 9390 名 ALS/FTD 患者和 4594 名对照的队列中，NUP50 中的罕见变异与 ALS 风险相关（P = 3.71.10；优势比 = 3.29；95%CI，1.37 至 7.87）。携带 NUP50 移码突变的一位患者的细胞显示出 NUP50 水平降低。NUP50 的缺失导致培养神经元死亡，并导致果蝇和斑马鱼出现运动缺陷。因此，我们的研究确定了神经元中剪接的改变在 ALS 中是关键的，并提供了将核孔缺陷与 ALS 联系起来的遗传证据。
