Tobisawa Shinsuke, Hozumi Yasukazu, Arawaka Shigeki, Koyama Shingo, Wada Manabu, Nagai Makiko, Aoki Masashi, Itoyama Yasuto, Goto Kaoru, Kato Takeo
Third Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
Biochem Biophys Res Commun. 2003 Apr 4;303(2):496-503. doi: 10.1016/s0006-291x(03)00353-x.
Mutations in a Cu, Zn-superoxide dismutase (SOD1) cause motor neuron death in human familial amyotrophic lateral sclerosis (FALS) and its mouse model, suggesting that mutant SOD1 has a toxic effect on motor neurons. However, the question of how the toxic function is gained has not been answered. Here, we report that the mutant SOD1s linked to FALS, but not wild-type SOD1, aggregated in association with the endoplasmic reticulum (ER) and induced ER stress in the cDNA-transfected COS7 cells. These cells showed an aberrant intracellular localization of mitochondria and microtubules, which might lead to a functional disturbance of the cells. Motor neurons of the spinal cord in transgenic mice with a FALS-linked mutant SOD1 also showed a marked increase of GRP78/BiP, an ER-resident chaperone, just before the onset of motor symptoms. These data suggest that ER stress is involved in the pathogenesis of FALS with an SOD1 mutation.
铜锌超氧化物歧化酶（SOD1）的突变在人类家族性肌萎缩侧索硬化症（FALS）及其小鼠模型中导致运动神经元死亡，这表明突变型SOD1对运动神经元具有毒性作用。然而，毒性功能是如何获得的问题尚未得到解答。在此，我们报告与FALS相关的突变型SOD1而非野生型SOD1与内质网（ER）结合聚集，并在cDNA转染的COS7细胞中诱导内质网应激。这些细胞显示出线粒体和微管的异常细胞内定位，这可能导致细胞功能紊乱。具有与FALS相关的突变型SOD1的转基因小鼠脊髓中的运动神经元在运动症状出现之前也显示出内质网驻留伴侣蛋白GRP78/BiP的显著增加。这些数据表明内质网应激参与了SOD1突变型FALS的发病机制。
