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在ALS中,可替代的细胞质SFPQ异型具有降低的相分离潜力

Jacob Neeves^1,2, Marija Petrić Howe^1,2, Oliver J Ziff^1,2

¹Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.

Science advances

|August 22, 2025

概括

在ALS中,SFPQ (富含proline和glutamine的拼接因子) 的改变增加了另一个异型,altSFPQ. 这个altSFPQ对SFPQ有所贡献

科学领域:

分子生物学
神经科学
遗传学

背景情况:

富含普罗林和谷氨酸的剪接因子 (SFPQ) 是一种具有已确定的核功能的关键RNA结合蛋白.
新出现的证据表明SFPQ也在细胞质中起作用.
异常的SFPQ表达和局部化在肌缩侧面硬化症 (ALS) 中观察到,但缺乏机制性解释.

研究的目的:

研究SFPQ在ALS中变化的表达和局部化的分子机制.
识别和描述与ALS病变相关的新型SFPQmRNA异型.

主要方法:

在ALS患者样本和模型中分析SFPQ拼接模式.
替代SFPQ (altSFPQ) mRNA异型的特征,包括其局部化和翻译.
评估altSFPQ蛋白质特性,例如相分离潜力和蛋白质相互作用.

主要成果:

在ALS中鉴定出改变的SFPQ拼接,导致产生缺乏核定位序列的altSFPQ异型.
证明altSFPQmRNA有助于SFPQ自我调节,并且主要在细胞质中转化.
在家族性和零星性ALS模型中观察到SFPQ的降低和altSFPQ转录水平的增加.
发现与正规SFPQ相比,altSFPQ蛋白具有降低的相分离潜力和改变的蛋白结合.

结论:

这项研究为ALS中SFPQ的核转细胞质再分配提供了机制基础.
altSFPQ异型代表了ALS的新型致病因子,影响SFPQ的细胞功能并导致疾病.
这些发现为RNA结合蛋白在像ALS这样的神经退行性疾病中的作用提供了新的见解.

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