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缺乏NLS结合的Kapβ2通过与C9orf72-ALS/FTD双重复的选择性相互作用减少神经毒性

Kevin M Kim¹, Amandeep Girdhar¹, Maria E Cicardi²

¹Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.

Communications biology

|January 2, 2025

概括

一种新的Kapβ2突变选择性地向涉及C9-ALS/FTD的有毒氨酸丰富二重复蛋白 (R-DPRs). 这种有针对性的方法可以减轻R-DPR的神经毒性,而不会破坏正常的RNA结合蛋白功能,从而提供一种潜在的治疗策略.

科学领域:

神经科学是一个神经科学.
分子生物学分子生物学
生物化学生物化学

背景情况:

富含氨酸的二聚重复蛋白 (R-DPRs) 是C9orf72相关的肌缩侧硬化症和前性痴呆症 (C9-ALS/FTD) 的有毒罪祸首.
通过干扰RNA结合蛋白 (RBPs) 的相位行为,R-DPRs诱导细胞损伤.

研究的目的:

为了研究R-DPR诱导的异常RBP相位过渡的机制,使用FUS作为模型RBP.
使用Kapβ2开发一种治疗策略,可以选择性地向R-DPR,而不会影响本源RBP功能.

主要方法:

利用FUS作为一种模型RNA结合蛋白来研究R-DPR相互作用.
设计了一个核定位信号 (NLS) 结合缺陷的Kapβ2突变 (Kapβ2_W460A:W730A).
评估了Kapβ2_W460A:W730A与R-DPR的选择性结合及其对FUS相分离和应力颗粒形成的影响.

主要成果:

野生类型的Kapβ2减轻了R-DPR诱导的相位过渡,但可能会对本地RBPs产生非目标效应.
Kapβ2_W460A:W730A选择性地与R-DPR相互作用,而不会破坏正常的FUS相分离.
Kapβ2_W460A:W730A 防止在压力颗粒中的聚 (GR) 丰富,并减少R-DPR的神经毒性.

结论:

一种经过修改的Kapβ2蛋白 (Kapβ2_W460A:W730A) 表明有毒R-DPRs的选择性向.
这种选择性向减轻了R-DPR诱导的神经毒性,为C9-ALS/FTD提供了一个有希望的治疗途径.

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