Increased mitochondrial antioxidative activity or decreased oxygen free radical propagation prevent mutant SOD1-mediated motor neuron cell death and increase amyotrophic lateral sclerosis-like transgenic mouse survival.
The molecular mechanisms of selective motor neuron degeneration in human amyotrophic lateral sclerosis (ALS) disease remain largely unknown and effective therapies are not currently available. Mitochondrial dysfunction is an early event of motor neuron degeneration in transgenic mice overexpressing mutant superoxide dismutase (SOD)1 gene and mitochondrial abnormality is observed in human ALS patients. In an in vitro cell culture system, we demonstrated that infection of mouse NSC-34 motor neuron-like cells with adenovirus containing mutant G93A-SOD1 gene increased cellular oxidative stress, mitochondrial dysfunction, cytochrome c release and motor neuron cell death. Cells pretreated with highly oxidizable polyunsaturated fatty acid elevated lipid peroxidation and synergistically exacerbated motor neuron-like cell death with mutant G93A-SOD1 but not with wild-type SOD1. Similarly, overexpression of mitochondrial antioxidative genes, MnSOD and GPX4 by stable transfection significantly increased NSC-34 motor neuron-like cell resistance to mutant SOD1. Pre-incubation of cells with spin trapping molecule, 5',5'-dimethylpryrroline-N-oxide (DMPO), prevented mutant SOD1-mediated mitochondrial dysfunction and cell death. Furthermore, treatment of mutant G93A-SOD1 transgenic mice with DMPO significantly delayed paralysis and increased survival. These findings suggest a causal relationship between enhanced oxidative stress and mutant SOD1-mediated motor neuron degeneration, considering that enhanced oxygen free radical production results from the SOD1 structural alterations. Molecular approaches aimed at increasing mitochondrial antioxidative activity or effectively blocking oxidative stress propagation can be potentially useful in the clinical management of human ALS disease.
Liu
Rugao
R
Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Kentucky 40202, USA. r0Liu002@gwise.louisville.edu
Li
Baolin
B
Flanagan
Shawn W
SW
Oberley
Larry W
LW
Gozal
David
D
Qiu
Mengsheng
M
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000401:mortality; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D015996:Survival Rate
C025634:5,5-dimethylpyrrolidin-2-one-1-oxide; D000975:Antioxidants; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003576:Electron Transport Complex IV