Redox Systems May Play Crucial Role in Familial ALS Development, Scientists Say

Researchers at the Karolinska Institute in Sweden and the University of Barcelona in Spain studied the contribution of cellular redox environment changes to the stability and integrity of SOD1, a protein implicated in the development and progression of familial amyotrophic lateral sclerosis (ALS).

A key finding was that mutations in the protein influence the ability of cellular redox systems to regulate SOD1 and therefore, these systems may play a critical role in the pathogenesis of ALS.

The research paper, “Cellular redox systems impact the Aggregation of Cu-Zn Superoxide Dismutase linked to Familial Amyotrophic Lateral Sclerosis,” was published in The Journal of Biological Chemistry.

The presence of protein aggregates in the nervous tissue of patients is the hallmark of neurodegenerative diseases. In the case of familial ALS, superoxide dismutase 1 (SOD1) aggregates in the spinal cord of patients and transgenic mice carrying mutations of this protein. It is estimated that 20 percent of inherited mutations that cause ALS are mutations of SOD1. In turn, familial ALS represents 10 percent of all cases of ALS.

These aggregates are known to be caused by protein misfolding, a process that results in the incorrect form of the protein that results in aggregation and, as a result, neuronal death. The oxidation state of structural molecules within the protein is essential to its structure and stability. The redox potential within the cells is mainly controlled by Trx and Grx systems, and changes in this heavily influence the oxidation state and, therefore, the conformation of the normal and mutant forms of SOD1.

Because the role of the cellular redox environment in SOD1 folding and aggregation remains poorly understood, researchers studied the effects in a series of experiments. They showed that both Trx and Grx systems can alter the oxidized forms of certain SOD1 mutants and that normal SOD1 is much more resistant to reduction by both systems.

Furthermore, treatment with inhibitors of these redox systems led to the increase of SOD1 aggregates in cells transfected with mutants, but not in cells transfected with normal SOD1.

“These results strongly suggest that Trx and Grx systems are the key regulators for hSOD1 aggregation and may play critical roles in the pathogenesis of ALS,” the researchers concluded.