Oxidation-induced Misfolding and Aggregation of Superoxide Dismutase and Its Implications for Amyotrophic Lateral Sclerosis

TLDR

Intracellular aggregates of Cu/Zn superoxide dismutase (SOD1) in motor neurons are a hallmark of ALS, and although SOD1 is abundant in all cells, its unusually long half‑life in motor neurons may predispose it to damage. The study aimed to determine how oxidative modification drives misfolding and aggregation of wild‑type and ALS‑associated SOD1 mutants. By oxidizing specific histidine residues that coordinate metal ions, the authors examined the resulting structural destabilization and aggregation propensity of SOD1. Zinc‑deficient wild‑type SOD1 and mutant proteins aggregated readily upon oxidation, and the data support a model in which oxidation of metal‑binding histidines promotes SOD1 aggregation, explaining its accumulation in ALS motor neurons.

Abstract

The presence of intracellular aggregates that contain Cu/Zn superoxide dismutase (SOD1) in spinal cord motor neurons is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Although SOD1 is abundant in all cells, its half-life in motor neurons far exceeds that in any other cell type. On the basis of the premise that the long half-life of the protein increases the potential for oxidative damage, we investigated the effects of oxidation on misfolding/aggregation of SOD1 and ALS-associated SOD1 mutants. Zinc-deficient wild-type SOD1 and SOD1 mutants were extremely prone to form visible aggregates upon oxidation as compared with wild-type holo-protein. Oxidation of select histidine residues that bind metals in the active site mediates SOD1 aggregation. Our results provide a plausible model to explain the accumulation of SOD1 aggregates in motor neurons affected in ALS.