Overexpression of SOD1 protects vulnerable motor neurons after spinal cord injury by attenuating mitochondrial cytochrome c release.
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.
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D002467:Cell Nucleus / Q000648:ultrastructure; D003574:Cytochrome c Group / Q000378:metabolism*; D019610:Cytoprotection; D053938:DNA Fragmentation; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D013116:Spinal Cord / Q000737:chemistry; D013118:Spinal Cord Diseases / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism
D003574:Cytochrome c Group; D013481:Superoxides; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1