Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Zn-superoxide dismutase.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor function and eventual death as a result of degeneration of motor neurons in the spinal cord and brain. The discovery of mutations in SOD1, the gene encoding the antioxidant enzyme Cu/Zn-superoxide dismutase (CuZnSOD), in a subset of ALS patients has led to new insight into the pathophysiology of ALS. Utilizing a novel adenovirus gene delivery system, our laboratory has developed a human cell culture model using chemically differentiated neuroblastoma cells to investigate how mutations in SOD1 lead to neuronal death. Expression of mutant SOD1 (G37R) resulted in a time and dose-related death of differentiated neuroblastoma cells. This cell death was inhibited by overexpression of the antioxidant enzyme manganese superoxide dismutase (MnSOD). These observations support the hypothesis that mutant SOD1-associated neuronal death is associated with alterations in oxidative stress, and since MnSOD is a mitochondrial enzyme, suggest that mitochondria play a key role in disease pathogenesis. Our findings in this model of inhibition of mutant SOD1-associated death by MnSOD represent an unique approach to explore the underlying mechanisms of mutant SOD1 cytotoxicity and can be used to identify potential therapeutic agents for further testing.
Flanagan
Shawn W
SW
Free Radical and Radiation Biology Program, The University of Iowa, Iowa City 52242, USA. shawn-flanagan@uiowa.edu
Anderson
Richard D
RD
Ross
Mark A
MA
Oberley
Larry W
LW
D000256:Adenoviridae / Q000235:genetics; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003300:Copper; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D008345:Manganese / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D014162:Transfection; D015032:Zinc
D008345:Manganese; D003300:Copper; D013482:Superoxide Dismutase; D015032:Zinc