Harmine Acts as an Indirect Inhibitor of Intracellular Protein Aggregation

Abstract

Protein aggregation and oxidative stress are two pathological hallmarks of a number of protein misfolding diseases, including Huntington's disease (HD). Whether protein aggregation precedes elevation of oxidative stress or follows it remains ambiguous. We have investigated the role of harmine, a beta-carboline alkaloid, in aggregation of a mutant huntingtin fragment (103Q-htt) in a yeast model of HD. We observed that harmine was able to decrease intracellular aggregation of 103Q-htt, and this reduction was higher than that observed with trehalose, a conventional protein stabilizer. The presence of harmine also decreased prion formation. Decreased protein aggregation was accompanied by reduction in oxidative stress. However, harmine had no effect on aggregation of the mutant huntingtin fragment in vitro. Thus, based on experimental data, we conclude that the antioxidant harmine lowers aggregation-induced elevation in oxidative stress, which slows down intracellular protein aggregation.