Exp Mol Med.
2007 Oct;39(5):574-582.
Calcium-influx increases SOD1 aggregates via nitric oxide in cultured motor neurons
- Affiliations
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- 1School of Chemical and Biological Engineering, Institute of Chemical ProcessesSeoul National University, Seoul 151-741, Korea.
- 2Department of Neurology, Seoul National University College of MedicineSeoul 110-799, Korea. kimmanho@snu.ac.kr
- 3Seoul Science High School, Seoul 110-530, Korea.
- 4Department of Neurology, College of Medicine, Kangwon National UniversityChuncheon 200-701, Korea.
Abstract
- Familial amyotrophic lateral sclerosis (fALS) is caused by mutations in Cu/Zn-superoxide dismutase (SOD1), and SOD1 aggregation and calcium toxicity are involved in neuronal death. However, the effect of altered calcium homeostasis on the SOD1 aggregation is unknown. To investigate whether calcium triggers mutant SOD1 aggregation in vitro, human mutant SOD1 (G93A) was transfected into motor neuronal cell line (VSC 4.1 cells). These cells were then treated with calcium ionophore A23187 or agents that induce intracellular calcium release like cyclic ADP ribose, ryanodine or thapsigargin. A23187 was found to increase mutant SOD1 aggregation and neuronal nitric oxide synthase (nNOS) expression. Moreover, the NOS inhibitor (L-NAME) and a NO-dependent cyclic GMP cascade inhibitor (ODQ) reduced SOD1 aggregation, whereas an exogenous NO donor (GSNO) increased mutant SOD1 aggregation, which was also prevented by NOS or cGMP cascade inhibitor. Our data demonstrate that calcium-influx increases SOD1 aggregation by upregulating NO in cultured motor neuronal cells.
Keyword
MeSH Terms
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Amyotrophic Lateral Sclerosis/genetics/metabolism
Animals
Calcimycin/pharmacology
Calcium/*metabolism
Calpain/metabolism
Caspase 3/metabolism
Cell Line
Humans
Ionophores/pharmacology
Motor Neurons/*metabolism
Multiprotein Complexes
Mutation
Nitric Oxide/*metabolism
Rats
Recombinant Proteins/chemistry/genetics/metabolism
Superoxide Dismutase/chemistry/genetics/*metabolism
Transfection
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