Sugawara Taku, Lewén Anders, Gasche Yvan, Yu Fengshan, Chan Pak H
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California CA 94305-5487, USA.
FASEB J. 2002 Dec;16(14):1997-9. doi: 10.1096/fj.02-0251fje. Epub 2002 Oct 4.
Defective Cu,Zn-superoxide dismutase (SOD1) is responsible for some types of amyotrophic lateral sclerosis, and ventral horn motor neurons (VMN) have been shown to die through a mitochondria-dependent apoptotic pathway after chronic exposure to high levels of reactive oxygen species (ROS). VMN are also selectively vulnerable to mild spinal cord injury (SCI); however, the involvement of SOD1, ROS, and apoptosis in their death has not been clarified. Mild compression SCI was induced in SOD1-overexpressing transgenic rats and wild-type littermates. Superoxide production, mitochondrial release of cytochrome c, and activation of caspase-9 were examined, and apoptotic DNA injury was also characterized. In the wild-type animals, increased superoxide production, mitochondrial release of cytochrome c, and cleaved caspase-9 were observed exclusively in VMN after SCI. Subsequently, a majority of VMN (75%) selectively underwent delayed apoptotic cell death. Transgenic animals showed less superoxide production, mitochondrial cytochrome c release, and caspase-9 activation, resulting in death of only 45% of the VMN. These results suggest that the ROS-initiated mitochondrial signaling pathway possibly plays a pivotal role in apoptotic VMN death after SCI and that increased levels of SOD1 in VMN reduce oxidative stress, thereby attenuating the activation of the pathway and delayed cell death.
缺陷型铜锌超氧化物歧化酶（SOD1）与某些类型的肌萎缩侧索硬化症有关，并且已表明腹角运动神经元（VMN）在长期暴露于高水平活性氧（ROS）后会通过线粒体依赖性凋亡途径死亡。VMN对轻度脊髓损伤（SCI）也具有选择性易损性；然而，SOD1、ROS和凋亡在其死亡中的作用尚未阐明。在过表达SOD1的转基因大鼠和野生型同窝仔鼠中诱导轻度压迫性SCI。检测了超氧化物生成、细胞色素c的线粒体释放和caspase-9的激活，并对凋亡性DNA损伤进行了表征。在野生型动物中，SCI后仅在VMN中观察到超氧化物生成增加、细胞色素c的线粒体释放和裂解的caspase-9。随后，大多数VMN（75%）选择性地发生延迟凋亡性细胞死亡。转基因动物的超氧化物生成、线粒体细胞色素c释放和caspase-9激活较少，导致只有45%的VMN死亡。这些结果表明，ROS启动的线粒体信号通路可能在SCI后凋亡性VMN死亡中起关键作用，并且VMN中SOD1水平的升高可降低氧化应激，从而减弱该通路的激活和延迟细胞死亡。
