TARDBP and familial amyotrophic lateral sclerosis: The concept that SOD1 misfolding and toxicity is downstream of TDP-43 is consistent with reports that the emergence of the sporadic ALS syndrome may be preceded by six mathematically defined preclinical “steps” (68) but that familial amyotrophic lateral sclerosis mutations in TDP-43 are best captured by a model comprising four steps and that SOD1 mutations apparently require only two steps (69), suggesting that WT SOD1 may be downstream of other events in sporadic ALS pathogenesis, such as TDP-43 aggregation.