Mutant Cu/Zn Superoxide Dismutase (A4V) Turnover Is Altered in Cells Containing Inclusions.

SOD1 mutations account for ∼20% of familial amyotrophic lateral sclerosis (ALS) cases in which the hallmark pathological feature is insoluble SOD1 aggregates within motor neurons. Here, we investigated the degradation and synthesis of mutant SOD1 to determine whether the aggregation of mutant SOD1 affects these processes. We confirm that, in general, the degradation of mutant SOD1 occurs at a significantly faster rate than wild-type SOD1. We also report that the turnover and synthesis of mutant SOD1 is impaired in the presence of insoluble SOD1 aggregates. However, the timing of aggregation of SOD1 did not coincide with UPS dysfunction. Together, these results reveal the impact of SOD1 aggregation on protein degradation pathways, highlighting the importance of the UPS in preventing neurodegenerative disorders such as ALS.