Calcium-influx increases SOD1 aggregates via nitric oxide in cultured motor neurons.
- Author:
Hyun Jung KIM
1
;
Wooseok IM
;
Seungchan KIM
;
Sung Hun KIM
;
Jung Jun SUNG
;
Manho KIM
;
Kwang Woo LEE
Author Information
1. School of Chemical and Biological Engineering, Institute of Chemical ProcessesSeoul National University, Seoul 151-741, Korea.
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
amyotrophic lateral sclerosis;
calcium;
motor neuron disease;
nitric oxide;
nitric oxide synthase;
superoxide dismutase
- MeSH:
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
- From:Experimental & Molecular Medicine
2007;39(5):574-582
- CountryRepublic of Korea
- Language:English
-
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.
