AQAMAN, a bisamidine-based inhibitor of toxic protein inclusions in neurons, ameliorates cytotoxicity in polyglutamine disease models

摘要: Polyglutamine (polyQ) diseases are a group of dominantly inherited neurodegenerative disorders caused by the expansion an unstable CAG repeat in coding region affected genes. Hallmarks polyQ include accumulation misfolded protein aggregates, leading to neuronal degeneration and cell death. PolyQ currently incurable, highlighting urgent need for approaches that inhibit formation disaggregate cytotoxic inclusions. Here, we screened bisamidine-based inhibitors can We demonstrated one inhibitor, AQAMAN, prevents aggregation promotes de-aggregation self-assembled proteins several models diseases. Using immunocytochemistry, found AQAMAN significantly reduces specifically suppresses protein–induced recombinant purified (thioredoxin–Huntingtin–Q46), further interferes with self-assembly, preventing aggregation, dissociates preformed aggregates cell-free system. Remarkably, feeding Drosophila expressing expanded disease polyQ-induced neurodegeneration vivo. In addition, using activators autophagy pathway, AQAMAN's cytoprotective effect against toxicity is autophagy-dependent. summary, have identified as potential therapeutic combating Our findings highlight importance pathway clearing harmful proteins.