Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron degeneration, with misfolded and aggregated Cu/Zn-superoxide dismutase (SOD1) proteins implicated in its pathogenesis. Previous studies have demonstrated that copper and zinc ions play essential roles in the proper folding and structural stability of SOD1. Specifically, dissociation of a zinc ion from SOD1 has been identified as a critical factor promoting the formation of SOD1 oligomers and amyloid-like fibrils.1, 2 This observation led to the hypothesis that mutations causing reduced zinc affinity or intracellular zinc deficiency may trigger SOD1 aggregation, thus contributing to ALS onset.
However, this hypothesis encounters significant questions. First, some ALS-related SOD1 mutations cause disease without substantially lowering zinc affinity.3 Second, given the extremely high zinc affinity of SOD1,4 it remains unclear if intracellular zinc levels could drop sufficiently to induce significant zinc dissociation. These uncertainties suggest that the loss of zinc ions alone may not fully explain SOD1 aggregation observed in ALS.
To explore alternative mechanisms, we examined the effects of excess zinc ions on SOD1 behavior in vitro. Intriguingly, our results revealed that increasing the molar ratio of zinc ions relative to SOD1 induced robust formation of insoluble SOD1 aggregates. This finding strongly suggests that SOD1 aggregation can also occur under conditions of zinc excess, rather than merely zinc deficiency. Based on these observations, we propose that perturbation of the intracellular balance between SOD1 and zinc ions - whether through deficiency or excess - may drive protein aggregation and thereby contribute to ALS pathogenesis.
Our study highlights the importance of maintaining a precise intracellular zinc equilibrium for SOD1 stability and provides a novel perspective on the molecular mechanisms underlying SOD1 aggregation in ALS. These insights underscore the complexity of metal homeostasis in ALS and suggest potential new therapeutic targets focusing on cellular metal ion regulation.