Bim links ER stress and apoptosis in cells expressing mutant SOD1 associated with amyotrophic lateral sclerosis.
Bim links ER stress and apoptosis in cells expressing mutant SOD1 associated with amyotrophic lateral sclerosis.
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DOI：
10.1371/journal.pone.0035413
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Nagley P
中科院分区：
文献类型：
--
作者：
Soo KY;Atkin JD;Farg M;Walker AK;Horne MK;Nagley P
内质网（ER）应激是肌萎缩侧索硬化（ALS）细胞死亡的重要途径。我们以前证明，ER应力与神经毒性相关的形成夹杂物的突变体铜，锌-超氧化物歧化酶1（SOD 1）。携带突变包涵体的细胞经历线粒体凋亡信号传导。在这里，我们证明了BH 3-only蛋白，Bim，是ER应激和线粒体凋亡之间的直接联系。在鼠神经母细胞瘤细胞系Neuro 2a中，携带突变的SOD 1包涵体，表达ER应激和凋亡的指标。通过siRNA敲低Bim显著减少了这些含有内含物的细胞中的核凋亡特征（但不影响含有内含物的细胞的总体比例）。此外，在Bim耗竭条件下，Bax向线粒体的募集和细胞色素c的再分布也减少。然而，上调CHOP，ER应激的标志物，并没有减少Bim敲低。显著地，通过siRNA敲低CHOP降低了携带突变SOD 1内含物的细胞中的凋亡程度。ER应激、CHOP上调和线粒体凋亡信号的Bim激活之间的这些顺序联系表明突变体SOD 1介导的细胞死亡的明确途径。
Endoplasmic reticulum (ER) stress is an important pathway to cell death in amyotrophic lateral sclerosis (ALS). We previously demonstrated that ER stress is linked to neurotoxicity associated with formation of inclusions of mutant Cu,Zn-superoxide dismutase 1 (SOD1). Cells bearing mutant inclusions undergo mitochondrial apoptotic signalling. Here, we demonstrate that the BH3-only protein, Bim, is a direct link between ER stress and mitochondrial apoptosis. In the murine neuroblastoma cell line, Neuro2a, bearing mutant SOD1 inclusions, indicators of both ER stress and apoptosis are expressed. Bim knockdown by siRNA significantly reduced nuclear apoptotic features in these inclusion-bearing cells (but did not affect the proportion of cells overall that bear inclusions). Further, both Bax recruitment to mitochondria and cytochrome c redistribution were also decreased under Bim-depletion conditions. However, upregulation of CHOP, a marker of ER stress, was not reduced by Bim knockdown. Significantly, knockdown of CHOP by siRNA reduced the extent of apoptosis in cells bearing mutant SOD1 inclusions. These sequential links between ER stress, CHOP upregulation, and Bim activation of mitochondrial apoptotic signalling indicate a clear pathway to cell death mediated by mutant SOD1.
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影响因子：
4.8
作者：
Atkin, Julie D.;Farg, Manal A.;Horne, Malcolm K.
通讯作者：
Horne, Malcolm K.
DOI：
10.1073/pnas.0438011100
发表时间：
2003-03-04
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0902505106
发表时间：
2009-05-12
影响因子：
11.1
作者：
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通讯作者：
Borchelt, David R.
影响因子：
10.8
作者：
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通讯作者：
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