Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor
neurons. About 10% of ALS cases are inherited (familial), and a large subset of them are caused by mutations in the gene
encoding the copper-zinc superoxide dismutase (SOD1). The detection of SOD1-positive inclusions in familial ALS patients
suggests the role of SOD1 aggregation underlying the pathology of familial ALS. Although SOD1 mutant proteins
are different in structure, stability and activity, they all exhibit a higher aggregation propensity than wild-type SOD1. We
here review the recent studies on the role of metallation states and disulfide status in the unfolding, misfolding, and aggregation
of SOD1. Investigations of the mechanism of SOD1 aggregation enhance our understanding of onset and progression
of ALS and have implications for therapeutic approaches for treating ALS.