Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1 (Retracted article. See vol. 292, pg. 12007, 2017)
Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1 (Retracted article. See vol. 292, pg. 12007, 2017)
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DOI：
10.1074/jbc.m603393200
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发表时间：
2006-10-06
影响因子：
4.8
通讯作者：
Horne, Malcolm K.
中科院分区：
文献类型：
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作者：
Atkin, Julie D.;Farg, Manal A.;Horne, Malcolm K.
铜/锌超氧化物歧化酶（SOD 1）的突变与家族性肌萎缩侧索硬化症（ALS）的运动神经元死亡的机制尚不清楚，虽然错误折叠的SOD 1聚集体通常与疾病有关。对转基因SOD 1（G93 A）ALS大鼠模型的蛋白质组学分析显示，腰髓中内质网（ER）驻留蛋白二硫键异构酶（PDI）家族成员显著上调。SOD 1突变体（mSOD 1）的表达导致运动神经元样NSC-34细胞中PDI的上调，而不是其他细胞系。使用杆菌肽抑制PDI增加了聚集体的产生，即使在不容易形成包涵体的野生型SOD 1转染子中，这表明PDI可以保护SOD 1免于聚集。此外，PDI与mSOD 1的细胞内聚集体共定位，并与野生型和mSOD 1结合。SOD 1也被发现在微粒体部分的细胞，尽管是一个主要的胞质酶，确认ER-高尔基体依赖性分泌。在SOD 1G 93 A小鼠中，在疾病期间也观察到未折叠蛋白反应实体的显著上调，包括半胱天冬酶-12、-9和-3裂解。因此，我们的研究结果牵连未折叠的蛋白质反应和ER应激诱导的细胞凋亡的病理生理学家族性ALS。本研究还提出了PDI可能是预防SOD 1聚集的治疗靶点的可能性。
Mutations in Cu/Zn superoxide dismutase (SOD1) are linked to motor neuron death in familial amyotrophic lateral sclerosis (ALS) by an unclear mechanism, although misfolded SOD1 aggregates are commonly associated with disease. Proteomic analysis of the transgenic SOD1(G93A) ALS rat model revealed significant up-regulation of endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI) family members in lumbar spinal cords. Expression of SOD1 mutants (mSOD1) led to an up-regulation of PDI in motor neuron-like NSC-34 cells but not other cell lines. Inhibition of PDI using bacitracin increased aggregate production, even in wild type SOD1 transfectants that do not readily form inclusions, suggesting PDI may protect SOD1 from aggregation. Moreover, PDI co-localized with intracellular aggregates of mSOD1 and bound to both wild type and mSOD1. SOD1 was also found in the microsomal fraction of cells despite being a predominantly cytosolic enzyme, confirming ER-Golgi-dependent secretion. In SOD1G93A mice, a significant up-regulation of unfolded protein response entities was also observed during disease, including caspase-12, -9, and -3 cleavage. Our findings therefore implicate unfolded protein response and ER stress-induced apoptosis in the pathophysiology of familial ALS. The possibility that PDI may be a therapeutic target to prevent SOD1 aggregation is also raised by this study.