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

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)170-177
Number of pages8
JournalJournal of Neurochemistry
Volume81
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Superoxide Dismutase
Cells
Amyotrophic Lateral Sclerosis
Enzymes
Antioxidants
Neurodegenerative diseases
Mitochondria
Gene encoding
Oxidative stress
Neuroblastoma
Cell death
Cytotoxicity
Cell culture
Neurons
Brain
Genes
Gene Transfer Techniques
Mutation
Motor Neurons
Adenoviridae

Keywords

  • Amyotrophic lateral sclerosis
  • Mitochondria
  • Neuroblastoma
  • Superoxide dismutase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Zn-superoxide dismutase. / Flanagan, Shawn W.; Anderson, Richard D.; Ross, Mark A; Oberley, Larry W.

In: Journal of Neurochemistry, Vol. 81, No. 1, 2002, p. 170-177.

Research output: Contribution to journalArticle

@article{3bdcc0cddced4420a54ba18ed5b219a7,
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.",
keywords = "Amyotrophic lateral sclerosis, Mitochondria, Neuroblastoma, Superoxide dismutase",
author = "Flanagan, {Shawn W.} and Anderson, {Richard D.} and Ross, {Mark A} and Oberley, {Larry W.}",
year = "2002",
doi = "10.1046/j.1471-4159.2002.00812.x",
language = "English (US)",
volume = "81",
pages = "170--177",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Zn-superoxide dismutase

AU - Flanagan, Shawn W.

AU - Anderson, Richard D.

AU - Ross, Mark A

AU - Oberley, Larry W.

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - Mitochondria

KW - Neuroblastoma

KW - Superoxide dismutase

UR - http://www.scopus.com/inward/record.url?scp=0036071852&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036071852&partnerID=8YFLogxK

U2 - 10.1046/j.1471-4159.2002.00812.x

DO - 10.1046/j.1471-4159.2002.00812.x

M3 - Article

C2 - 12067230

AN - SCOPUS:0036071852

VL - 81

SP - 170

EP - 177

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 1

ER -