Bisdemethoxycurcumin, a novel potent polyphenolic compound, effectively inhibits the formation of amyloid aggregates in ALS-associated hSOD1 mutant (L38R).

Protein misfolding is a biological process that leads to protein aggregation. Anomalous misfolding and aggregation of human superoxide dismutase (hSOD1) into amyloid aggregates is a characteristic feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative illness. Thus, focusing on the L38R mutant may be a wise decision to comprehend the SOD1 disease process in ALS. We suggest that Bisdemethoxycurcumin (BDMC) may be a strong anti-amyloidogenic polyphenol against L38R mutant aggregation. Protein stability, hydrophobicity, and flexibility were altered when BDMC was bound to the L38R mutant, as shown by molecular dynamic (MD) simulations and molecular docking. FTIR data shows α-Helix dominance in BDMC-containing samples, with reduced β-sheet and disordered peaks, indicating the decrease of aggregate species. ThT aggregation kinetics curves show BDMC reduces L38R mutant aggregation dose-dependently, with higher BDMC concentrations yielding greater reductions. TEM images showed various quantities of amorphous aggregates, but notably, 60 μM BDMC markedly reduced aggregate density, underscoring BDMC's inhibitory effect. Hemolysis tests revealed aggregate species in BDMC-treated samples were less toxic than in L38R mutant samples alone at the same concentrations and exposure times. Overall, BDMC has substantial potential to develop highly effective inhibitors that mitigate the risk of fatal ALS.