Neeves Jacob, Petrić Howe Marija, Ziff Oliver J, Callaghan Beth, Jutzi Daniel, Pal Koustav, Roumeliotis Theodoros I, Choudhary Jyoti, Isaacs Adrian M, Rigo Frank, Bennett C Frank, Ruepp Marc-David, Patani Rickie
Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Sci Adv. 2025 Aug 22;11(34):eadt4814. doi: 10.1126/sciadv.adt4814.
Splicing factor proline- and glutamine-rich (SFPQ) is an RNA binding protein that broadly regulates RNA metabolism. Although its nuclear roles are well studied, evidence of SFPQ's cytoplasmic functionality is emerging. Altered expression and nuclear-to-cytoplasmic redistribution of SFPQ have been recognized in amyotrophic lateral sclerosis (ALS) pathology, yet the mechanistic bases for these phenomena remain undetermined. We identified altered splicing in ALS, increasing the expression of an alternative mRNA isoform lacking a nuclear localization sequence, which we termed "." We find that mRNA contributes to SFPQ autoregulation and is highly unstable yet exhibits context-specific translation with cytoplasm-predominant localization. Notably, reduced canonical coincides with increased transcript expression in familial and sporadic ALS models, providing a mechanistic basis for SFPQ nuclear-to-cytoplasmic redistribution in patients with ALS. Last, we observe that the altSFPQ protein has reduced phase separation potential and differential protein binding compared to its canonical counterpart, providing insight into its mechanistic relevance to physiology and ALS pathogenesis.
富含脯氨酸和谷氨酰胺的剪接因子（SFPQ）是一种RNA结合蛋白，广泛调节RNA代谢。尽管其在细胞核中的作用已得到充分研究，但SFPQ在细胞质中的功能证据正在不断涌现。在肌萎缩侧索硬化症（ALS）病理中已认识到SFPQ的表达改变和核-质重新分布，然而这些现象的机制基础仍未确定。我们在ALS中发现了剪接改变，增加了一种缺乏核定位序列的可变mRNA异构体的表达，我们将其命名为“.”。我们发现mRNA有助于SFPQ的自我调节，高度不稳定，但在细胞质占主导地位的定位中表现出特定背景下的翻译。值得注意的是，在家族性和散发性ALS模型中，经典的减少与转录本表达增加同时出现，为ALS患者中SFPQ的核-质重新分布提供了机制基础。最后，我们观察到与经典对应物相比，altSFPQ蛋白的相分离潜力降低，蛋白质结合存在差异，这为其与生理学和ALS发病机制的机制相关性提供了见解。
