Phosphorylated and ubiquitinated TDP-43 pathological inclusions in ALS and FTLD-U are recapitulated in SH-SY5Y cells
Phosphorylated and ubiquitinated TDP-43 pathological inclusions in ALS and FTLD-U are recapitulated in SH-SY5Y cells
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DOI：
10.1016/j.febslet.2008.12.031
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发表时间：
2009-01-22
期刊：
影响因子：
3.5
通讯作者：
Hasegawa, Masato
中科院分区：
文献类型：
--
作者：
Nonaka, Takashi;Arai, Tetsuaki;Hasegawa, Masato
我们报道了SH-SY5Y细胞中43 kDa的TAR DNA结合蛋白(TDP-43)的磷酸化和泛素化聚集体，与肌萎缩侧索硬化症(ALS)和泛素化脑叶变性(FTLD-U)的脑组织相似。对核定位信号的两个候选序列进行了检查。缺失残基78-84导致TDP-43的胞质定位，而缺失残基187-192的突变体定位于细胞核，形成独特的点状结构。蛋白酶体抑制导致这些蛋白组装成磷酸化和泛素化的TDP-43聚集体。缺失突变体缺乏囊性纤维化跨膜传导调节因子外显子9的外显子跳跃活性。我们的结果提示，TDP-43的细胞内定位和蛋白酶体功能可能参与了TDP-43蛋白病变中包涵体的形成和神经变性。(C)2008年欧洲生化学会联合会。爱思唯尔出版公司版权所有。
We report phosphorylated and ubiquitinated aggregates of TAR DNA binding protein of 43 kDa (TDP-43) in SH-SY5Y cells similar to those in brains of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). Two candidate sequences for the nuclear localization signal were examined. Deletion of residues 78-84 resulted in cytoplasmic localization of TDP-43, whereas the mutant lacking residues 187-192 localized in nuclei, forming unique dot-like structures. Proteasome inhibition caused these to assemble into phosphorylated and ubiquitinated TDP-43 aggregates. The deletion mutants lacked the exon skipping activity of cystic fibrosis transmembrane conductance regulator (CFTR) exon 9. Our results suggest that intracellular localization of TDP-43 and proteasomal function may be involved in inclusion formation and neurodegeneration in TDP-43 proteinopathies. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.