Homocysteine induces oxidative cytotoxicity in Cu,Zn-superoxide dismutase mutant motor neuronal cell

Mutations in human Cu,Zn-superoxide dismutase (SODI) cause approximate to20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism of late-onset disease manifestation despite the innate mutation has no clear explanation. The relationship between homocysteine (HC) and amyotrophic lateral sclerosis (ALS) has not been investigated, in spite of the similarity in their pathogenesis. We investigated the effect of HC on the motor neuronal cell-line transfected with SODI of either wild-type or one of two mutant forms (G93A and A4V). In the MTT assay, HC induced significant cytotoxicity in A4V, but not in G93A, as compared with wild-type, even at the physiological concentration of 10 muM. This HC-induced cytotoxicity was inhibited by the antioxidant trolox and the Cu (I) chelator bathocuproinedisulfonate. Here we show that the vulnerability of the A4V mutant involves the cytotoxic copper-mediated pathway, and that HC may be a lifelong precipitating factor in some forms of FALS, suggesting the possible treatment modality with vitamin supplements.