Trehalose protects against glycation and aggregation of SOD1

Introduction: Amyotrophic lateral sclerosis (ALS) is a severe, progressive, and ultimately fatal neurodegenerative disease for which there is currently no cure. A common feature across all types of ALS is SOD1 proteopathy. According to our previous results,  methylglyoxal (MGO) has been shown to cause SOD1 aggregation. Neurons are generally more vulnerable to the toxic effects of MGO, a byproduct of glycolysis. The literature shows that trehalose protects against protein misfolding and aggregation. However, the protective effects of this sugar on MGO-mediated SOD1 aggregation have not been previously explored.

Objective: This work aimed to assess how effectively trehalose protects against the glycation and aggregation of SOD1 caused by MGO.

Material and Methods: In vitro aggregation experiments were conducted with WT and A4V SOD1, a mutant associated with ALS. The experiments were carried out at 37°C with shaking for one week, using treatments of 5 mM and 10 mM MGO, in the presence or absence of trehalose. The oligomerization state of SOD1 was evaluated using Western blotting and size exclusion chromatography. Additionally, glycated SOD1 was analyzed with an anti-MGO antibody.

Results and Discussion: In the presence of MGO, stable oligomers were observed for WT and A4V SOD1, while the mutant formed higher molecular mass species. Trehalose reduced the formation of these species and also lessened the glycation of SOD1.

Conclusion: Trehalose was able to protect SOD1 from glycation damage, preventing aggregation caused by MGO and demonstrating its potential as a therapeutic approach to treat ALS.