G(4)C(2) Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS/FTD.
G(4)C(2) Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS/FTD.
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DOI：
10.1016/j.neuron.2020.06.027
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发表时间：
2020-09-23
期刊：
影响因子：
16.2
通讯作者：
Rothstein JD
中科院分区：
文献类型：
--
作者：
Coyne AN;Zaepfel BL;Hayes L;Fitchman B;Salzberg Y;Luo EC;Bowen K;Trost H;Aigner S;Rigo F;Yeo GW;Harel A;Svendsen CN;Sareen D;Rothstein JD
尽管机制尚不明确，但在包括C9orf72 ALS/FTD在内的多种神经退行性疾病中，核胞质运输缺陷和特定核孔复合物相关蛋白的积累已被报道。利用超分辨率结构照明显微镜，我们探索了从C9orf72诱导的多能干细胞衍生神经元（iPSNs）分离的细胞核中核孔蛋白改变的机制。在评估的23个核孔蛋白中，我们观察到8个亚群的减少，包括核孔复合物支架的关键成分和跨膜核孔蛋白POM121。在C9orf72 iPSNs中，POM121的减少似乎引发了另外7种核孔蛋白表达的减少，最终影响Ran GTPase的定位和随后的细胞毒性。总的来说，我们的数据表明，扩增的C9orf72 ALS/FTD重复RNA的表达单独影响核POM121的表达，从而影响神经元细胞核内核孔蛋白水平的病理级联，最终影响下游神经元的存活。Coyne等人证明G4C2重复RNA启动了C9orf72神经元核孔复合物中POM121表达的减少。核POM121的减少会影响另外7种核孔蛋白的表达，从而改变核孔组成。这种核孔蛋白的联合减少影响核胞质转运蛋白的定位和神经元的存活。
Through mechanisms that remain poorly defined, defects in nucleocytoplasmic transport and accumulations of specific nuclear pore complex associated proteins have been reported in multiple neurodegenerative diseases including C9orf72 ALS/FTD. Using super resolution structured illumination microscopy, we have explored the mechanism by which nucleoporins are altered in nuclei isolated from C9orf72 induced pluripotent stem cell derived neurons (iPSNs). Of the twenty three nucleoporins evaluated, we observed a reduction in a subset of eight including key components of the nuclear pore complex scaffold and the transmembrane nucleoporin POM121. Reduction in POM121 appears to initiate a decrease in the expression of seven additional nucleoporins ultimately impacting the localization of Ran GTPase and subsequent cellular toxicity in C9orf72 iPSNs. Collectively, our data suggest that expression of expanded C9orf72 ALS/FTD repeat RNA alone impacts nuclear POM121 expression in the initiation of a pathological cascade affecting nucleoporin levels within neuronal nuclei and ultimately downstream neuronal survival. Coyne et al. demonstrate that G4C2 repeat RNA initiates a reduction of POM121 expression within C9orf72 neuronal nuclear pore complexes. Decreased nuclear POM121 impacts the expression of 7 additional nucleoporins resulting in altered nuclear pore composition. This combined nucleoporin reduction impacts the localization of nucleocytoplasmic transport proteins and neuronal survival.
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影响因子：
25
作者：
Chou CC;Zhang Y;Umoh ME;Vaughan SW;Lorenzini I;Liu F;Sayegh M;Donlin-Asp PG;Chen YH;Duong DM;Seyfried NT;Powers MA;Kukar T;Hales CM;Gearing M;Cairns NJ;Boylan KB;Dickson DW;Rademakers R;Zhang YJ;Petrucelli L;Sattler R;Zarnescu DC;Glass JD;Rossoll W
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影响因子：
2.1
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影响因子：
16.2
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通讯作者：
Lagier-Tourenne C