On this line, data obtained in models in vitro and in vivo indicate that soluble forms of mutant SOD1 initiate disease and larger aggregates are implicated only in rapidly progressing events in the final stages of disease, and thus it has been argued that disulfide bond formation is a secondary effect and not primarily causative for aggregate formation in ALS (Karch et al., 2009). This evidence concerns the gene SOD1 and amyotrophic lateral sclerosis.