Shang Jingwei, Yamashita Toru, Nakano Yumiko, Morihara Ryuta, Li Xianghong, Feng Tian, Liu Xia, Huang Yong, Fukui Yusuke, Hishikawa Nozomi, Ohta Yasuyuki, Abe Koji
Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kitaku, Okayama 700-8558, Japan.
Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kitaku, Okayama 700-8558, Japan.
Neuroscience. 2017 May 14;350:158-168. doi: 10.1016/j.neuroscience.2017.03.024. Epub 2017 Mar 24.
Nuclear pore complexes (NPCs) play important roles in traffic of molecules between the nucleus and cytoplasm, aberrant distributions of components of NPCs were demonstrated in C9orf72 amyotrophic lateral sclerosis (C9-ALS) patients, but it is elusive whether such abnormities are also the case with other cause of ALS disease. In the present study, we investigated the spatiotemporal distributions of RanGAP1 and 4 representative nucleoporins (GP210, NUP205, NUP107 and NUP50) of NPCs in human Cu/Zn superoxide dismutase-1 mutation transgenic (SOD1-Tg) mice and sporadic ALS patients. Compared with wild type (WT), these proteins displayed age-dependent and progressive nuclear precipitations, and cytoplasmic aberrant expressions in motor neurons of lumbar cord in SOD1-Tg mice from 10 to 18weeks (W). Double immunofluorescent analysis showed abnormal nuclear retention and apparent co-localizations of RanGAPl with NUP205 and NUP205 with NUPl07, meanwhile, GP210 with NUP205 mainly co-localized in the nuclear envelope (NE) of motor neurons. Furthermore, RanGAP1, GP210 and NUP50 showed similarly abnormal nuclear precipitations and cytoplasmic upregulations in SOD1-Tg mice and ALS patients, moreover, aberrant co-localizations of RanGAP1 with TDP-43 and NUP205 with TDP-43 were also observed in motor neurons. The present study indicated that the mislocalization of these proteins of NPCs may underlie the pathogenesis of ALS both in SOD1-Tg mice and human sporadic ALS patients, and these dysfunctions may be a fundamental pathway for ALS that is not specific only in C9-ALS but also in SOD1-ALS, which may be amenable to pharmacotherapeutic intervention.
核孔复合体（NPCs）在细胞核与细胞质之间的分子运输中发挥着重要作用。在C9orf72型肌萎缩侧索硬化症（C9-ALS）患者中已证实NPCs成分存在异常分布，但尚不清楚其他病因导致的肌萎缩侧索硬化症（ALS）是否也存在此类异常。在本研究中，我们调查了人铜/锌超氧化物歧化酶-1突变转基因（SOD1-Tg）小鼠和散发性ALS患者中RanGAP1以及NPCs的4种代表性核孔蛋白（GP210、NUP205、NUP107和NUP50）的时空分布。与野生型（WT）相比，这些蛋白在10至18周龄（W）的SOD1-Tg小鼠腰髓运动神经元中呈现出年龄依赖性和渐进性的核内沉淀以及细胞质异常表达。双重免疫荧光分析显示RanGAP1与NUP205、NUP205与NUP107存在异常的核内滞留和明显的共定位，同时，GP210与NUP205主要共定位于运动神经元的核膜（NE）。此外，RanGAP1、GP210和NUP50在SOD1-Tg小鼠和ALS患者中表现出相似的异常核内沉淀和细胞质上调，而且在运动神经元中还观察到RanGAP1与TDP-43、NUP205与TDP-43的异常共定位。本研究表明，NPCs这些蛋白的定位错误可能是SOD1-Tg小鼠和人类散发性ALS患者ALS发病机制的基础，并且这些功能障碍可能是ALS的一个基本途径，不仅在C9-ALS中具有特异性，在SOD1-ALS中也具有特异性，这可能适合药物治疗干预。
