Role of GSK-3β activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene

Seong-Ho Koh, Young Bae Lee, Kyung S. Kim, Hyun Jung Kim, Manho Kim, Young-Joo Lee, Juhan Kim, Kwang Woo Lee, Seung Hyun Kim

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Point mutations such as G93A and A4V in the human Cu/Zn-superoxide dismutase gene (hSOD1) cause familial amyotrophic lateral sclerosis (fALS). In spite of several theories to explain the pathogenic mechanisms, the mechanism remains largely unclear. Increased activity of glycogen synthase kinase-3 (GSK-3) has recently been emphasized as an important pathogenic mechanism of neurodegenerative diseases, including Alzheimer's disease and ALS. To investigate the effects of G93A or A4V mutations on the phosphatidylinositol-3- kinase (PI3-K)/Akt and GSK-3 pathway as well as the caspase-3 pathway, VSC4.1 motoneuron cells were transfected with G93A- or A4V-mutant types of hSOD1 (G93A and A4V cells, respectively) and, 24 h after neuronal differentiation, their viability and intracellular signals, including PIS-K/Akt, GSK-3, heat shock transcription factor-1 (HSTF-1), cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those of wild type (wild cells). Furthermore, to elucidate the role of the GSK-3β-mediated cell death mechanism, alterations of viability and intracellular signals in those mutant motoneurons were investigated after treating the cells with GSK-3β inhibitor. Compared with wild cells, viability was greatly reduced in the G93A and A4V cells. However, the treatment of G93A and A4V cells with GSK-3β inhibitor increased their viability by activating HSTF-1 and by reducing cytochrome c release, caspase-3 activation and PARP cleavage. However, the treatment did not affect the expression of PI3-K/Akt and GSK-3β. These results suggest that the G93A or A4V mutations inhibit PI3-K/Akt and activate GSK-3β and caspase-3, thus becoming vulnerable to oxidative stress, and that the GSK-3β-mediated cell death mechanism is important in G93A and A4V cell death.

Original languageEnglish
Pages (from-to)301-309
Number of pages9
JournalEuropean Journal of Neuroscience
Volume22
Issue number2
DOIs
StatePublished - 2005 Jul 1

Fingerprint

Glycogen Synthase Kinase 3
Motor Activity
Cell Death
Phosphatidylinositol 3-Kinase
Genes
Caspase 3
Poly(ADP-ribose) Polymerases
Motor Neurons
Cytochromes c1
Mutation
Point Mutation
Neurodegenerative Diseases
Cell Survival
Alzheimer Disease
Oxidative Stress

Keywords

  • ALS
  • Apoptosis
  • GSK-3
  • Oxidative stress
  • Pathophysiology

Cite this

Koh, Seong-Ho ; Lee, Young Bae ; Kim, Kyung S. ; Kim, Hyun Jung ; Kim, Manho ; Lee, Young-Joo ; Kim, Juhan ; Lee, Kwang Woo ; Kim, Seung Hyun. / Role of GSK-3β activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene. In: European Journal of Neuroscience. 2005 ; Vol. 22, No. 2. pp. 301-309.
@article{0226c50a56294019802fed6dfe2b1b6c,
title = "Role of GSK-3β activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene",
abstract = "Point mutations such as G93A and A4V in the human Cu/Zn-superoxide dismutase gene (hSOD1) cause familial amyotrophic lateral sclerosis (fALS). In spite of several theories to explain the pathogenic mechanisms, the mechanism remains largely unclear. Increased activity of glycogen synthase kinase-3 (GSK-3) has recently been emphasized as an important pathogenic mechanism of neurodegenerative diseases, including Alzheimer's disease and ALS. To investigate the effects of G93A or A4V mutations on the phosphatidylinositol-3- kinase (PI3-K)/Akt and GSK-3 pathway as well as the caspase-3 pathway, VSC4.1 motoneuron cells were transfected with G93A- or A4V-mutant types of hSOD1 (G93A and A4V cells, respectively) and, 24 h after neuronal differentiation, their viability and intracellular signals, including PIS-K/Akt, GSK-3, heat shock transcription factor-1 (HSTF-1), cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those of wild type (wild cells). Furthermore, to elucidate the role of the GSK-3β-mediated cell death mechanism, alterations of viability and intracellular signals in those mutant motoneurons were investigated after treating the cells with GSK-3β inhibitor. Compared with wild cells, viability was greatly reduced in the G93A and A4V cells. However, the treatment of G93A and A4V cells with GSK-3β inhibitor increased their viability by activating HSTF-1 and by reducing cytochrome c release, caspase-3 activation and PARP cleavage. However, the treatment did not affect the expression of PI3-K/Akt and GSK-3β. These results suggest that the G93A or A4V mutations inhibit PI3-K/Akt and activate GSK-3β and caspase-3, thus becoming vulnerable to oxidative stress, and that the GSK-3β-mediated cell death mechanism is important in G93A and A4V cell death.",
keywords = "ALS, Apoptosis, GSK-3, Oxidative stress, Pathophysiology",
author = "Seong-Ho Koh and Lee, {Young Bae} and Kim, {Kyung S.} and Kim, {Hyun Jung} and Manho Kim and Young-Joo Lee and Juhan Kim and Lee, {Kwang Woo} and Kim, {Seung Hyun}",
year = "2005",
month = "7",
day = "1",
doi = "10.1111/j.1460-9568.2005.04191.x",
language = "English",
volume = "22",
pages = "301--309",
journal = "European Journal of Neuroscience",
issn = "0953-816X",
number = "2",

}

Role of GSK-3β activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene. / Koh, Seong-Ho; Lee, Young Bae; Kim, Kyung S.; Kim, Hyun Jung; Kim, Manho; Lee, Young-Joo; Kim, Juhan; Lee, Kwang Woo; Kim, Seung Hyun.

In: European Journal of Neuroscience, Vol. 22, No. 2, 01.07.2005, p. 301-309.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Role of GSK-3β activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene

AU - Koh, Seong-Ho

AU - Lee, Young Bae

AU - Kim, Kyung S.

AU - Kim, Hyun Jung

AU - Kim, Manho

AU - Lee, Young-Joo

AU - Kim, Juhan

AU - Lee, Kwang Woo

AU - Kim, Seung Hyun

PY - 2005/7/1

Y1 - 2005/7/1

N2 - Point mutations such as G93A and A4V in the human Cu/Zn-superoxide dismutase gene (hSOD1) cause familial amyotrophic lateral sclerosis (fALS). In spite of several theories to explain the pathogenic mechanisms, the mechanism remains largely unclear. Increased activity of glycogen synthase kinase-3 (GSK-3) has recently been emphasized as an important pathogenic mechanism of neurodegenerative diseases, including Alzheimer's disease and ALS. To investigate the effects of G93A or A4V mutations on the phosphatidylinositol-3- kinase (PI3-K)/Akt and GSK-3 pathway as well as the caspase-3 pathway, VSC4.1 motoneuron cells were transfected with G93A- or A4V-mutant types of hSOD1 (G93A and A4V cells, respectively) and, 24 h after neuronal differentiation, their viability and intracellular signals, including PIS-K/Akt, GSK-3, heat shock transcription factor-1 (HSTF-1), cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those of wild type (wild cells). Furthermore, to elucidate the role of the GSK-3β-mediated cell death mechanism, alterations of viability and intracellular signals in those mutant motoneurons were investigated after treating the cells with GSK-3β inhibitor. Compared with wild cells, viability was greatly reduced in the G93A and A4V cells. However, the treatment of G93A and A4V cells with GSK-3β inhibitor increased their viability by activating HSTF-1 and by reducing cytochrome c release, caspase-3 activation and PARP cleavage. However, the treatment did not affect the expression of PI3-K/Akt and GSK-3β. These results suggest that the G93A or A4V mutations inhibit PI3-K/Akt and activate GSK-3β and caspase-3, thus becoming vulnerable to oxidative stress, and that the GSK-3β-mediated cell death mechanism is important in G93A and A4V cell death.

AB - Point mutations such as G93A and A4V in the human Cu/Zn-superoxide dismutase gene (hSOD1) cause familial amyotrophic lateral sclerosis (fALS). In spite of several theories to explain the pathogenic mechanisms, the mechanism remains largely unclear. Increased activity of glycogen synthase kinase-3 (GSK-3) has recently been emphasized as an important pathogenic mechanism of neurodegenerative diseases, including Alzheimer's disease and ALS. To investigate the effects of G93A or A4V mutations on the phosphatidylinositol-3- kinase (PI3-K)/Akt and GSK-3 pathway as well as the caspase-3 pathway, VSC4.1 motoneuron cells were transfected with G93A- or A4V-mutant types of hSOD1 (G93A and A4V cells, respectively) and, 24 h after neuronal differentiation, their viability and intracellular signals, including PIS-K/Akt, GSK-3, heat shock transcription factor-1 (HSTF-1), cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those of wild type (wild cells). Furthermore, to elucidate the role of the GSK-3β-mediated cell death mechanism, alterations of viability and intracellular signals in those mutant motoneurons were investigated after treating the cells with GSK-3β inhibitor. Compared with wild cells, viability was greatly reduced in the G93A and A4V cells. However, the treatment of G93A and A4V cells with GSK-3β inhibitor increased their viability by activating HSTF-1 and by reducing cytochrome c release, caspase-3 activation and PARP cleavage. However, the treatment did not affect the expression of PI3-K/Akt and GSK-3β. These results suggest that the G93A or A4V mutations inhibit PI3-K/Akt and activate GSK-3β and caspase-3, thus becoming vulnerable to oxidative stress, and that the GSK-3β-mediated cell death mechanism is important in G93A and A4V cell death.

KW - ALS

KW - Apoptosis

KW - GSK-3

KW - Oxidative stress

KW - Pathophysiology

UR - http://www.scopus.com/inward/record.url?scp=23244436178&partnerID=8YFLogxK

U2 - 10.1111/j.1460-9568.2005.04191.x

DO - 10.1111/j.1460-9568.2005.04191.x

M3 - Article

C2 - 16045483

AN - SCOPUS:23244436178

VL - 22

SP - 301

EP - 309

JO - European Journal of Neuroscience

JF - European Journal of Neuroscience

SN - 0953-816X

IS - 2

ER -