Overexpression of nuclear FUS induces neuronal cell death
Overexpression of nuclear FUS induces neuronal cell death
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核FUS过度表达诱导神经元细胞死亡
DOI：
10.1016/j.neuroscience.2014.12.007
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发表时间：
2015
期刊：
影响因子：
3.3
通讯作者：
Hiroaki Suzuki and Masaaki Matsuoka
中科院分区：
文献类型：
--
作者：
Hiroaki Suzuki;Yoshio Shibagaki;Seisuke Hattori;and Masaaki Matsuoka;Hiroaki Suzuki and Masaaki Matsuoka
肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）是临床、遗传和病理上重叠的神经退行性疾病。融合肉瘤（FUS）的失调已被假设为导致ALS和FTLD的功能获得和/或功能丧失的方式。然而，ALS/FTLD的发病机制和FUS功能障碍之间的联系尚未明确确定。在这项研究中，我们发现，FUS的过度表达，但不敲低内源性FUS表达，诱导运动神经元NSC 34细胞和原代皮层神经元死亡，通过线粒体凋亡途径，可能独立的反式反应DNA结合蛋白-43。此外，我们发现，核FUS，而不是胞质FUS，是负责FUS诱导的神经元细胞死亡。这些观察结果表明，核中FUS的功能获得有助于FUS相关神经退行性疾病的发病机制。
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative diseases that overlap clinically, genetically, and pathologically. Dysregulation of fused in sarcoma (FUS) has been hypothesized to cause ALS and FTLD in gain-of-function and/or loss-of-function manners. However, the link between the pathogenesis of ALS/FTLD and dysfunction of FUS has not been clearly determined. In this study, we found that overexpression of FUS, but not knocking-down of endogenous FUS expression, induces death in motor neuronal NSC34 cells and primary cortical neurons via the mitochondrial apoptotic pathway, possibly independently of transactive response DNA-binding protein-43. Furthermore, we found that nuclear FUS, but not cytoplasmic FUS, is responsible for FUS-induced neuronal cell death. These observations suggest that the gain-of-function of FUS in the nucleus contributes to the pathogenesis of FUS-linked neurodegenerative diseases.