耶鲁大学医学院Junjie U. Guo研究组取得一项新突破。他们研制了异常剪接导致ALS/FTD中C9orf72重复扩增。该研究于2025年8月11日发表于国际一流学术期刊《自然—神经科学》杂志上。

通过选择性地从患者来源的成纤维细胞和神经元中捕获和测序含有NRE的RNA (NRE-capture-seq)，研究小组发现，与之前的模型相反，C9 NRE作为延长的外显子1的一部分被保留，这是由于其下游可选的5'剪接位点的不同。这些异常剪接异构体在C9-ALS/FTD大脑中积累，它们的产生是由富含丝氨酸/精氨酸的剪接因子1 （SRSF1）促进的。针对SRSF1或异常C9剪接异构体的反义寡核苷酸降低了DPR的水平。总之，他们的发现揭示了异常剪接在含NRE RNA的生物发生中的关键作用，并展示了针对这些致病转录物的潜在治疗策略。

据了解，C9orf72 （C9）基因第一个注释内含子内的核苷酸重复扩增（NRE）（GGGGCC）n是肌萎缩性侧索硬化症（ALS）和额颞叶痴呆（FTD）的常见主题。虽然先前的研究表明C9 NRE产生几种有毒的二肽重复（DPR）蛋白，但内含子RNA片段进入细胞质翻译机制的机制尚不清楚。

附：英文原文

Title: Aberrant splicing exonizes C9orf72 repeat expansion in ALS/FTD

Author: Yang, Suzhou, Wijegunawardana, Denethi, Sheth, Udit, Veire, Austin M., Salgado, Juliana M. S., Arab, Tanina, Agrawal, Manasi, Zhou, Jeffrey, Pereira, Joo D., Gendron, Tania F., Guo, Junjie U.

Issue&Volume: 2025-08-11

Abstract: A nucleotide repeat expansion (NRE) (GGGGCC)n within the first annotated intron of the C9orf72 (C9) gene is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While previous studies have shown that C9 NRE produces several toxic dipeptide repeat (DPR) proteins, the mechanism by which an intronic RNA segment can access the cytoplasmic translation machinery remains unclear. By selectively capturing and sequencing NRE-containing RNAs (NRE-capture-seq) from patient-derived fibroblasts and neurons, we found that, in contrast to previous models, C9 NRE is retained as part of an extended exon 1 due to the usage of various downstream alternative 5′ splice sites. These aberrant splice isoforms accumulate in C9-ALS/FTD brains, and their production is promoted by serine/arginine-rich splicing factor 1 (SRSF1). Antisense oligonucleotides targeting either SRSF1 or the aberrant C9 splice isoforms reduced the levels of DPR. Together, our findings revealed a crucial role of aberrant splicing in the biogenesis of NRE-containing RNAs and demonstrated potential therapeutic strategies to target these pathogenic transcripts.

DOI: 10.1038/s41593-025-02039-5

Source: https://www.nature.com/articles/s41593-025-02039-5