Gallic acid inhibits filament formation and promotes the disassembly of superoxide dismutase 1, a protein involved in the pathogenesis of amyotrophic lateral sclerosis

Abstract

Superoxide dismutase 1 (SOD1) forms amyloid-like filaments in motor neurons, contributing to the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) and leading to neuronal cell death. Earlier studies identified Epigallocatechin gallate (EGCG) as an effective inhibitor of SOD1 filaments. This study explored the potential of natural compounds to inhibit SOD1 filament formation as an ALS treatment strategy. Our investigation revealed that gallic acid, a soluble constituent of tannic acid and a hydrolysis product of EGCG, disrupts SOD1 filament formation, similar to EGCG. Furthermore, gallic acid demonstrated the ability to dismantle pre-existing SOD1 protein filaments. The study unveiled the inhibitory potential of red wine, a dietary source of tannic acid, and showed that tannic acid, when treated with tannase from lactobacilli, can enhance the inhibition against SOD1 filament formation. The findings were validated using isothermal titration calorimetry (ITC) and molecular dynamics (MD) simulations, suggesting that gallic acid can bind to both the soluble and filamentous forms of SOD1 protein. This interaction could elucidate the mechanism by which SOD1 filament formation is inhibited. In conclusion, the study unveils the molecular mechanism by which gallic acid inhibits the formation of SOD1 filaments. Our results suggest that gallic acid, a hydrolysis product of red wine, may be employed as a functional food ingredient to mitigate neurodegenerative diseases caused by protein filaments, such as ALS.