S-Space College of Medicine/School of Medicine (의과대학/대학원) Anatomy (해부학전공) Journal Papers (저널논문_해부학전공)
Impairment of Nuclear Factor-κB Activation Increased Glutamate Excitotoxicity in a Motoneuron-Neuroblastoma Hybrid Cell Line Expressing Mutant (G93A) Cu/Zn-Superoxide Dismutase
- Pyo, Jung-Soo; Ko, Young San; Kim, Woo Ho; Kim, Manho; Nam, Seon Young; Cho, Sung Jin; Lee, Byung Lan; Baik, Tai-Kyoung; Chung, Hee-Yong; Lee, Kwang-Woo
- Issue Date
- JOURNAL OF NEUROSCIENCE RESEARCH; Vol.88(11); 2494-2503
- familial amyotrophic lateral sclerosis; nuclear factor-κB; glutamate excitotoxicity; mutant Cu/Zn superoxide dismutase; motor neurons
- Mutations in the superoxide dismutase 1 (SOD1) gene are linked to glutamate excitotoxicity in familial amyotrophic lateral sclerosis (fALS), but the underlying mechanism remains unclear. We investigated whether nuclear factor-kappa B (NE-kappa B) activation is involved in glutamate excitotoxicity by using motor neuron neuroblastoma hybrid cells that expressed a mutant (G93A) SOD1 (mtSOD1) or wild-type SOD1 (wtSOD1). MtSOD1 cells were more vulnerable to glutamate excitotoxicity than wtSOD1 cells and showed higher NE-kappa B activity, higher nuclear cRel expression, and lower nuclear RelA expression under basal conditions. Glutamate treatment increased NF-kappa B activation along with nuclear expressions of RelA and cRel in wtSOD1 cells but induced only weak nuclear RelA expression in mtSOD1 cells. Suppression of NF-kappa B activation using transfection of the superrepressive mutant form of l kappa B alpha (Ml kappa B alpha) inhibited nuclear RelA expression in both types of SOD1 cells, which increased glutamate excitotoxicity in wtSOD1 cells but not in mtS0D1 cells. Furthermore, immunohistochemistry confirmed stronger RelA immunoreactivity in the nuclei of motor neurons of spinal cord in wild-type SOD1 transgenic mice than in those in SOD1 G93A transgenic mice. In addition, we found that glutamate treatment decreased XIAP expression and increased caspase-3 activity in mtSOD1 cells and mIKBet-overexpressing wtSOD1 cells. Our results suggest that glutamate excitotoxicity in motor neurons of SOD1-linked fALS is attributable, at least in part, to the impairment of l kappa B alpha-dependent RelA activation and subsequent apoptosis mediated by XIAP inhibition and caspase-3 activation.
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