Pathogenic superoxide dismutase structure, folding, aggregation and turnover

Abstract

Significant advances have been made during the past two years toward an understanding of the molecular basis for how mutations in human cytosolic copper-zinc superoxide dismutase (SOD1) cause the inherited form of amyotrophic lateral sclerosis (ALS). Biophysical studies suggest that the pathogenic mutations destabilize loop or beta-barrel structural elements of the protein. With few exceptions, the loss of metal ions and reduction of the intrasubunit disulfide bond enhance this destabilization. In mouse models of the disease, the formation of visible aggregates containing mutant SOD1 occurs relatively late in the lifespan, hinting that the quality control and protein turnover systems of motor neurons eventually become overwhelmed or compromised. Studies probing SOD1 turnover have suggested the possibility that proteolytic breakdown products may play a role in pathogenesis.