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

Cited 19 time in Web of Science Cited 19 time in Scopus
Authors
Koh, Seong-Ho; Roh, Hakjae; Lee, Sang Mok; Kim, Hyun-Jung; Kim, Manho; Lee, Kwang Woo; Kim, Hee-Tae; Kim, Juhan; Kim, Seung Hyun
Issue Date
2005-06-06
Publisher
Elsevier
Citation
Toxicology. 2005 Sep 15;213(1-2):45-55.
Keywords
1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/*metabolismAmyotrophic Lateral Sclerosis/enzymologyApoptosis/*physiologyBlotting, WesternCaspase 3Caspases/metabolismCell Survival/drug effectsChromones/pharmacologyEnzyme Activation/drug effectsGlycogen Synthase Kinase 3/metabolismHumansMorpholines/pharmacologyMotor Neurons/cytology/drug effects/*enzymologyPoint MutationPoly(ADP-ribose) Polymerases/metabolismProtein Kinase Inhibitors/pharmacologyProtein-Serine-Threonine Kinases/metabolismProto-Oncogene Proteins/metabolismProto-Oncogene Proteins c-aktSignal TransductionSuperoxide Dismutase/genetics/*metabolism
Abstract
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.
ISSN
0300-483X (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15996807

https://hdl.handle.net/10371/15225
DOI
https://doi.org/10.1016/j.tox.2005.05.009
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Neurology (신경과학교실)Journal Papers (저널논문_신경과학교실)
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