TDP-43 physically interacts with amyotrophic lateral sclerosis-linked mutant CuZn superoxide dismutase
TDP-43 physically interacts with amyotrophic lateral sclerosis-linked mutant CuZn superoxide dismutase
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DOI：
10.1016/j.neuint.2010.09.010
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发表时间：
2010-12-01
影响因子：
4.2
通讯作者：
Kabuta, Tomohiro
中科院分区：
文献类型：
--
作者：
Higashi, Shinji;Tsuchiya, Yukihiro;Kabuta, Tomohiro
CuZn超氧化物歧化酶（SOD 1）和TAR DNA结合蛋白43（TDP-43）基因的突变分别与家族性肌萎缩侧索硬化症ALS 1和ALS 10相关。此外，TDP-43是在散发性ALS（SALS）中观察到的泛素化聚集体的主要组分蛋白。然而，目前还不清楚这些ALS组是否部分具有共同的发病机制。使用培养的细胞和G93 A突变型SOD 1转基因小鼠，通过免疫共沉淀测定，SOD 1型与TDP-43相互作用。SOD 1内负责这种相互作用的区域是二聚体界面，即N-和C-末端区域。43具有或不具有核定位序列与突变体SOD 1相互作用使用培养细胞的细胞分级分离测定显示突变体SOD 1是定位于胞质组分中，但不在核组分中检测到TDP-43，这表明突变SOD 1与胞质中的TDP-43相互作用。突变SOD 1过表达导致突变SOD 1的量增加，并在一定程度上导致去污剂中其相互作用蛋白包括TDP-43的量增加。这些结果表明突变SOD 1可以通过物理相互作用影响其相互作用蛋白质包括TDP-43的溶解性/不溶性我们的发现可能有助于理解SALS ALS 1和ALS 10之间的联系（C）。2010爱思唯尔有限公司保留所有权利
Mutations in the CuZn superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP-43) genes are linked to familial amyotrophic lateral sclerosis ALS1 and ALS10 respectively In addition TDP-43 is a major component protein of the ubiquitinated aggregates observed in sporadic ALS (SALS) patients However it remains unclear whether these ALS groups partly have a shared pathogenesis In the present study we demonstrate that mutant SOD1 but not wild-type SOD1 interacts with TDP-43 by co-immunoprecipitation assays using cultured cells and G93A mutant SOD1 transgenic mice The region responsible for this interaction within SOD1 is the dimer Interface namely the N- and C-terminal regions Deletion mutants of TDP-43 with or without nuclear localization sequence Interacted with mutant SOD1 Cell fractionation assays using cultured cells showed that mutant SOD1 was localized in the cytosolic fraction but not in the nuclear fraction TDP-43 was detected both in the nuclear and cytosolic fractions suggesting that mutant SOD1 interacts with TDP-43 in the cytoplasm Mutant SOD1 overexpression led to an Increased amount of mutant SOD1 and to some extent its interacting proteins including TDP-43 in the detergent-insoluble fraction These results indicate that mutant SOD1 could affect the solubility/insolubility of its interacting proteins including TDP-43 through physical interactions Our findings may contribute to the understanding of links among SALS ALS1 and ALS10 (C) 2010 Elsevier Ltd All rights reserved