Zinc and copper in the pathogenesis of amyotrophic lateral sclerosis

1. Missense mutations in the gene encoding Cu,Zn superoxide dismutase (SOD1) are responsible for causing one form of familial amyotrophic lateral sclerosis (FALS) linked to chromosome 21q. 2. Mutant SOD1-induced disease is clearly related to a toxic gain of function for the abnormal enzyme, and recent work has begun to investigate the mechanisms underlying this toxicity. In addition to its well known and likely beneficial dismutase activity, wild type SOD1 also possesses the ability to participate in other enzymatic reactions that may be injurious to cells including peroxidation or nitration. 3. Many of the SOD1 mutations associated with FALS appear to increase the likelihood that the enzyme will perform either one of these potentially harmful functions resulting in increased hydroxyl radical formation or the addition of nitro groups to tyrosine residues within cellular proteins. 4. Because several in vitro experiments have suggested that the extent of SOD1's ability to perform peroxidase and nitration reactions is dependent on the degree of copper and or zinc binding within the enzyme, these metals have become a focus of interest for understanding the exact mechanisms underlying motor neuron dysfunction in FALS as.