J Korean Neurol Assoc.  2005 Apr;23(2):249-256.

Role of Glycogen Synthase Kinase-3 in Motor Neuronal Cell Death Mechanism of in Vitro Familial ALS Model (G94A, A4V mutant motoneuron)

  • 1Department of Neurology, Hanyang University College of Medicine, Seoul, Korea. kimsh1@hanyang.ac.kr
  • 2Department of Neurology, Bundang Jesaeng Hospital, Gyeonggi, Korea.
  • 3Department of Neurology, Seoul National University College of Medicine, Seoul, Korea.


G93A or A4V mutations in the human Cu/Zn- superoxide dismutase gene (hSOD1) cause familial amyotrophic lateral sclerosis (fALS). However, it has not yet clearly understood how these bring about fALS. We investigated the effects of the G93A or A4V mutations in hSOD1 on the phosphatydilinositol-3-kinase (PI3K)/Akt and glycogen synthase kinase-3 (GSK-3) pathway, and effects of GSK-3 inhibitor on the G93A- or A4V-mutant cells. METHODS: To evaluate those effects, VSC4.1 motoneuron cells were transfected with G93A- or A4V-mutant types of hSOD1 (G93A and A4V cells, respectively) with/without GSK-3 inhibitor were compared with them transfected with wild type (wild cells) in cell viability and intracellular signals, including PI3K/Akt, GSK-3, and caspase-3, 24 hours after neuronal differentiation. RESULTS: Compared with wild cells, MTT assay revealed a greatly reduced viability in G93A and A4V cells without GSK-3 inhibitor. However, treatment with GSK-3 inhibitor increased the viability of G93A and A4V cells. Western blotting showed that PI3K and pAkt were decreased, and GSK-3 and caspase-3 were increased in G93A and A4V cells, and that GSK-3 inhibitor treatment reduced caspase-3 but did not affected PI3K, Akt and GSK-3. CONCLUSIONS: These results suggest that the G93A or A4V mutations induce inhibition of PI3K/Akt and activation of GSK-3 and caspase-3 resulting the vulnerability to oxidative stress, and that GSK-3 mediated cell death mechanism is important in G93A and A4V cell death.


ALS; Superoxide dismutase; Phosphatydilinositol-3-kinase; Glycogen synthase kinase-3

MeSH Terms

Amyotrophic Lateral Sclerosis
Blotting, Western
Caspase 3
Cell Death*
Cell Survival
Glycogen Synthase Kinase 3
Glycogen Synthase*
Motor Neurons*
Oxidative Stress
Superoxide Dismutase
Caspase 3
Glycogen Synthase
Glycogen Synthase Kinase 3
Superoxide Dismutase
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