title: Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Zn-superoxide dismutase.
abstract: 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.
authors.affiliation: Free Radical and Radiation Biology Program, The University of Iowa, Iowa City 52242, USA. shawn-flanagan@uiowa.edu
authors.forename: Shawn W
authors.initials: SW
authors.lastname: Flanagan
authors.forename: Richard D
authors.initials: RD
authors.lastname: Anderson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ross
authors.forename: Larry W
authors.initials: LW
authors.lastname: Oberley
mesh_terms: 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
chemical_list: D008345:Manganese; D003300:Copper; D013482:Superoxide Dismutase; D015032:Zinc