Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Zn-superoxide dismutase

Shawn W Flanagan; Richard D Anderson; Mark A Ross; Larry W Oberley

doi:10.1046/j.1471-4159.2002.00812.x

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Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Zn-superoxide dismutase

Journal article

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Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Zn-superoxide dismutase

Shawn W Flanagan, Richard D Anderson, Mark A Ross and Larry W Oberley

Journal of neurochemistry, Vol.81(1), pp.170-177

04/2002

DOI: 10.1046/j.1471-4159.2002.00812.x

PMID: 12067230

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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.

Cell Differentiation

Gene Expression

Oxidative Stress

Transfection

Zinc

Adenoviridae - genetics

Amino Acid Substitution

Amyotrophic Lateral Sclerosis - enzymology

Cell Death - drug effects

Cell Line

Cell Survival - drug effects

Copper

Gene Transfer Techniques

Genetic Vectors - genetics

Genetic Vectors - pharmacology

Humans

Manganese - metabolism

Mitochondria - enzymology

Neuroblastoma - enzymology

Neuroblastoma - pathology

Neurons - enzymology

Neurons - pathology

Superoxide Dismutase - genetics

Superoxide Dismutase - metabolism

Superoxide Dismutase - pharmacology

Details

Title: Subtitle: Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Zn-superoxide dismutase
Creators: Shawn W Flanagan - Free Radical and Radiation Biology Program, and
Richard D Anderson - University of Iowa
Mark A Ross - University of Kentucky
Larry W Oberley - Free Radical and Radiation Biology Program, and
Resource Type: Journal article
Publication Details: Journal of neurochemistry, Vol.81(1), pp.170-177
DOI: 10.1046/j.1471-4159.2002.00812.x
PMID: 12067230
NLM abbreviation: J Neurochem
ISSN: 0022-3042
eISSN: 1471-4159
Grant note: T32 AG00214 / NIA NIH HHS
Language: English
Date published: 04/2002
Academic Unit: Health, Sport, and Human Physiology
Record Identifier: 9984259657802771

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