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 scle rosis (FALS) linked to chromosome 21q. 2. Mutant SOD1-induced disease is clearly related to a toxic gain of functi on for the abnormal enzyme, and recent work has begun to investigate the me chanisms underlying this toxicity. In addition to its well known and likely beneficial dismutase activity, wild type SOD1 also possesses the ability t o participate in other enzymatic reactions that may be injurious to cells i ncluding peroxidation or nitration. 3. Many of the SOD1 mutations associated with FALS appear to increase the l ikelihood that the enzyme will perform either one of these potentially harm ful functions resulting in increased hydroxyl radical formation or the addi tion of nitro groups to tyrosine residues within cellular proteins. 4. Because several in vitro experiments have suggested that the extent of S OD1's ability to perform peroxidase and nitration reactions is dependent on the degree of copper and or zinc binding within the enzyme, these metals h ave become a focus of interest for understanding the exact mechanisms under lying motor neuron dysfunction in FALS as.