P150glued-associated disorders are caused by activation of intrinsic apoptotic pathway.
P150glued-associated disorders are caused by activation of intrinsic apoptotic pathway.
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DOI：
10.1371/journal.pone.0094645
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hattori N
中科院分区：
文献类型：
--
作者：
Ishikawa K;Saiki S;Furuya N;Yamada D;Imamichi Y;Li Y;Kawajiri S;Sasaki H;Koike M;Tsuboi Y;Hattori N
p150glued 突变会导致遗传性运动神经病伴声带麻痹 (HMN7B) 和佩里综合征 (PS)。在这里，我们表明 p150glued 突变体的过度表达和内源性 p150glued 的敲低都会诱导细胞凋亡。含有 HMN7B 或 PS 突变的 p150glued 质粒的过度表达会导致细胞质 p150glued 阳性聚集体，并与细胞死亡相关。含有突变型 p150glued 聚集体的细胞经历了细胞凋亡，其特征是裂解的 caspase-3 或膜联蛋白 V 阳性细胞增加，并且通过 zVAD-fmk（泛 caspase 抑制剂）应用和 caspase-3 siRNA 敲低来减弱。此外，突变体p150glued的过度表达降低了线粒体膜电位，增加了线粒体外膜转位酶（Tom20）蛋白的水平，表明受损线粒体的积累。重要的是，内源性 p150glued 的 siRNA 敲低通过 caspase-8 激活独立诱导细胞凋亡，并且与线粒体形态变化无关。同时敲除内源性 p150glued 和突变体 p150glued 的过表达具有累加的细胞凋亡诱导作用。这些发现表明，p150glued 毒性功能的获得和生理功能的丧失均可导致细胞凋亡，并可能是 p150glued 相关疾病的发病机制。
Mutations in p150glued cause hereditary motor neuropathy with vocal cord paralysis (HMN7B) and Perry syndrome (PS). Here we show that both overexpression of p150glued mutants and knockdown of endogenous p150glued induce apoptosis. Overexpression of a p150glued plasmid containing either a HMN7B or PS mutation resulted in cytoplasmic p150glued-positive aggregates and was associated with cell death. Cells containing mutant p150glued aggregates underwent apoptosis that was characterized by an increase in cleaved caspase-3- or Annexin V-positive cells and was attenuated by both zVAD-fmk (a pan-caspase inhibitor) application and caspase-3 siRNA knockdown. In addition, overexpression of mutant p150glued decreased mitochondrial membrane potentials and increased levels of translocase of the mitochondrial outer membrane (Tom20) protein, indicating accumulation of damaged mitochondria. Importantly, siRNA knockdown of endogenous p150glued independently induced apoptosis via caspase-8 activation and was not associated with mitochondrial morphological changes. Simultaneous knockdown of endogenous p150glued and overexpression of mutant p150glued had additive apoptosis induction effects. These findings suggest that both p150glued gain-of-toxic-function and loss-of-physiological-function can cause apoptosis and may underlie the pathogenesis of p150glued-associated disorders.
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影响因子：
16.2
作者：
Moughamian AJ;Holzbaur EL
通讯作者：
Holzbaur EL
影响因子：
30.8
作者：
Farrer MJ;Hulihan MM;Kachergus JM;Dächsel JC;Stoessl AJ;Grantier LL;Calne S;Calne DB;Lechevalier B;Chapon F;Tsuboi Y;Yamada T;Gutmann L;Elibol B;Bhatia KP;Wider C;Vilariño-Güell C;Ross OA;Brown LA;Castanedes-Casey M;Dickson DW;Wszolek ZK
通讯作者：
Wszolek ZK
影响因子：
13.3
作者：
Saiki, Shinji;Sasazawa, Yukiko;Hattori, Nobutaka
通讯作者：
Hattori, Nobutaka
影响因子：
3.5
作者：
Ravikumar, B;Duden, R;Rubinsztein, DC
通讯作者：
Rubinsztein, DC
DOI：
10.1083/jcb.136.1.215
发表时间：
1997-01-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
McCarthy NJ;Whyte MK;Gilbert CS;Evan GI
通讯作者：
Evan GI