Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Istituto Auxologico Italiano, IRCCS, Department of Neurology - Stroke Unit and Laboratory of Neuroscience, Milan, Italy.
Nat Commun. 2019 Aug 23;10(1):3827. doi: 10.1038/s41467-019-11837-y.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS and other neurodegenerative diseases, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here we show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity, nuclear import, and downstream pathways such as mRNA post-transcriptional regulation. Importantly, we demonstrate that modulation of actin homeostasis can rescue nuclear pore instability and dysfunction caused by mutant PFN1 as well as by C9ORF72 repeat expansion, the most common mutation in ALS patients. Collectively, our data link NCT defects to ALS-associated cellular pathology and propose the regulation of actin homeostasis as a novel therapeutic strategy for ALS and other neurodegenerative diseases.
肌萎缩侧索硬化症（ALS）是一种病因不明的致命神经退行性疾病。虽然核质转运（NCT）缺陷可能是 ALS 和其他神经退行性疾病发病机制的核心，但调节核孔功能的分子机制在很大程度上仍然未知。在这里，我们表明肌动蛋白聚合的遗传和药理学调节会破坏核孔的完整性、核输入以及 mRNA 转录后调节等下游途径。重要的是，我们证明肌动蛋白动态平衡的调节可以挽救由 PFN1 突变以及 ALS 患者中最常见的 C9ORF72 重复扩展引起的核孔不稳定和功能障碍。总的来说，我们的数据将 NCT 缺陷与 ALS 相关的细胞病理学联系起来，并提出调节肌动蛋白动态平衡作为 ALS 和其他神经退行性疾病的一种新的治疗策略。
