METHODS OF MODULATING RADICAL FORMATION BY MUTANT CuZnSOD ENZYMES

摘要

Familial amyotrophic lateral sclerosis (FALS)-associated mutant CuZnSODs, A4V and G93A, have been discovered to catalyze the generation of hydroxyl radical from hydrogen peroxide at higher rates than that of wild type CuZnSOD. The copper chelator diethyldithiocarbamate (DDC) has been found to inhibit both radical generation and SOD activity of mutant CuZnSODs A4V and G93A at DDC concentrations significantly lower than those required to inhibit wild type CuZnSOD enzyme. In a neural cell culture model of FALS, DDC reverses the effect of four FALS-associated mutants, but does not alter the survival of cells expressing only wild type CuZnSOD. Thus, radical formation may be modulated and ALS treated in subjects with a mutant CuZnSOD enzyme by the administration of copper chelating agents. Treatment can also be affected by the administration of radical scavenging agents, or the administration of expression inhibitors specific for the mutant genes.