Effect of Familial Amyotrophic Lateral Sclerosis-associated Cu, Zn-superox-ide Dismutase Mutation on Neural Differentiation in Motor Neuronal Cells

ABSTRACT

BACKGROUND: Mutations in the human Cu, Zn-superoxide dismutase(SOD1) gene have been identified in some cases of familial amyotrophic lateral sclerosis(ALS). The aim of this study is to delineate the effect of the SOD1 mutation on neural differentiation, and to investigate the mechanism of neuronal death. METHODS: We studied motorneuron-neurob-lastoma hybrid cells(VSC 4.1) expressing wild type or mutant SOD1(G93A, A4V) during differentiation by dibutyryl cAMP and aphidicolin. RESULTS: Mutant cells(G93A) revealed a decreased viability compared with the control cells, mainly in the early stage ofdifferentiation. The release of cytochrome c and increased nuclear fragmentation were observed. However, cell death was not protected by nonselective caspase inhibitor(z-VAD-fmk), but by the antioxi-dant( Trolox). CONCLUSIONS: The results suggest that oxidative stress may be the main mechanism of neuronal death, particularly in the early stage of differentiation.