Pathogenesis of Amyotrophic Lateral Sclerosis in neuroblastoma cell-cultural model

Abstract

Familial Amyotrophic lateral sclerosis is a hereditary disease with more than 60 mutations found in Cu/Zn superoxide dismutase (SOD1) gene. The cause of this disease remains a mystery. Here we report that an environmental mutagen induces SOD1 mutation specifically in neural-derived cells, SH-SY5Y, but not in breast adenocarcinoma cells, MCF7. Sequencing of RT-PCR amplified SOD1 cDNA revealed that 6 of 7 mutations were G-to-A or A-to-G transitions. Further study on the microsatellite instability showed that SH-SY5Y and MCF7 cells have a different pattern in two out of the four-microsatellite DNA markers and suggested an association of the DNA repair activity with the susceptibility of these cells to SOD1 mutation. Our study provide the first evidence to support a possibility that an environmental mutagen can cause neuronal specific SOD1 mutation with a pattern of mutation similar to that seen in the majority of familial ALS pedigrees. This, coupled with the reported low DNA repair enzyme activity in the brain, may play a part in the etiology of the ALS. Supported by Liu Po Shan/Dr. Vincent Liu endowment fund