Accounts for 5-10% of cases of ALS.
20% of familial cases are caused by a dominantly inherited mutation in the protein Cu/Zn Superoxide dismutase (SOD1). The ala-to-val substitution (A4V) is the most common mutation and results in aggressive disease (mean survival 1yr post-diagnosis). Mutant SOD1 is also a key component of protein aggregates in ALS.
SOD1 converts superoxide radicals to hydrogen peroxide and oxygen.
SOD1 is a metalloprotein (proteins with a metal ion co-factor) and is a key enzyme involved in anti-oxidant defence mechanisms. It is found in the cytosol, nucleus and mitochondrial membrane.
More than 140 mutations in the SOD1 gene have been identified (confirmed in transgenic animal models- which have strengthened our understanding of SOD1 and ALS). Early research has shown that the mechanism of mutated SOD1 is NOT via a loss of function/enzyme activity (SOD1 KO mice do not develop ALS). Therefore, mutations cause SOD1 to gain a toxic property.