The cytosolic enzyme Cu,Zn-superoxide dismutase (SOD1) is an intriguing enzyme. It is one of the most important antioxidant defenses but can also present pro-oxidant activities, such as the bicarbonate-dependent peroxidase activity. On the other hand, the human enzyme (hSOD1) is a small protein (153 amino acids and 1 copper and 1 zinc ion per monomer), which in the native state is a remarkably stable non covalent homodimer highly resistant to detergents and proteolysis. Nevertheless, point mutations of hSOD1 (>150 have been described) are associated with the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) (http://alsod.iop.kcl.ac.uk/). As is the case of other neurodegenerative diseases, protein misfolding and aggregation is a hallmark of ALS. Yet, the precise mechanism of SOD1 aggregation is currently unknown. Previous work by our group and others has raised the possibility that the bicarbonate-dependent peroxidase activity of human SOD1 (hSOD1) could result in the oxidation and aggregation of hSOD1. The goal of this project is to characterize the initial steps of hSOD1 aggregation-likely as a result of protein unfolding/misfolding-upon oxidation during the bicarbonate-dependent peroxidase activity.
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