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 language | English |
|---|---|
| Pages (from-to) | 301-309 |
| Number of pages | 9 |
| Journal | European Journal of Neuroscience |
| Volume | 22 |
| Issue number | 2 |
| DOIs | |
| State | Published - 2005 Jul 1 |
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Keywords
- ALS
- Apoptosis
- GSK-3
- Oxidative stress
- Pathophysiology
Cite this
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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 journal › Article
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 -