Phosphatidylinositol 3-kinase activator reduces motor neuronal cell death induced by G93A or A4V mutant SOD1 gene

• DOI: 10.1016/j.tox.2005.05.009
• Publication Date: 2005-07-06T22:02:27Z
• Authors: Seong-Ho Koh; Hakjae Roh; Sang Mok Lee; Hyun-Jung Kim; Manho Kim; Kwang Woo Lee; Hee-Tae Kim; Juhan Kim; Seung Hyun Kim
• Keywords: Motor Neurons; 0301 basic medicine; Glycogen Synthase Kinase 3 beta; Caspase 3; Cell Survival; Morpholines; Amyotrophic Lateral Sclerosis; Blotting, Western; Apoptosis; Protein Serine-Threonine Kinases; Enzyme Activation; Glycogen Synthase Kinase 3; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Chromones; Caspases; Proto-Oncogene Proteins; Humans; Point Mutation; Poly(ADP-ribose) Polymerases; Protein Kinase Inhibitors; Phosphoinositide-3 Kinase Inhibitors

The primary pathogenic mechanism of amyotrophic lateral sclerosis (ALS) remains largely unclear. We recently observed that motoneuron cell death mediated by G93A or A4V mutant SOD1, causing familial ALS, was related with decrease of survival signals, such as phosphatidylinositol 3-kinase (PI3-K) and Akt, which play a pivotal role in neuronal survival. Using a G93A or A4V mutant SOD1 transfected VSC4.1 motoneuron cells (G93A or A4V cells, respectively), we presently investigated whether PI3-K activator could reduce mutant SOD1-mediated motoneuron cell death. To investigate the effect of PI3-K activator on viability of G93A and A4V cells, these cells were treated with 10, 50 or 100ng/ml PI3-K activator for 24h and viability and intracellular signals, including Akt, glycogen synthase kinase-3 (GSK-3), heat shock transcription factor-1 (HSTF-1), cytosolic cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those without treatment (control). Compared with non-treated control G93A or A4V cells, the PI3-K activator treatment increased their viability by enhancing the survival signals, including pAkt, pGSK-3, and by inhibiting the death signals, including caspase-3 activation and PARP cleavage. These results suggest that PI3-K activator protects G93A or A4V cells from mutant SOD1-mediated motoneuron cell death by both activating survival signals and inactivating death signals.