Structural Conversion of Serotonin into Amyloid-like Nanoassemblies Conceptualizes an Unexplored Neurotoxicity Risk

The neuromodulator 5-hydroxytryptamine, known as serotonin, plays a key regulatory role in the central nervous system and peripheral organs; however, several research revelations have indicated a direct link between the oxidation of serotonin and a plethora of detrimental consequences. Hence, the question of how several neuronal and non-neuronal complications originate via serotonin oxidation remains an important area of investigation. Here, we show the autoxidation-driven structural conversion of serotonin into hemolytic and cytotoxic amyloid-like nanoassemblies under physiological conditions. We also observed the catalysis of serotonin oxidation in the presence of Aβ_1-42 amyloid fibrils and Cu(II) ions. The serotonin nanostructures generated from its spontaneous and amyloid-mediated oxidation exhibited typical structural and functional characteristics of amyloid entities, and their effective internalization in neuroblastoma cells caused cell-damaging effects via cytosolic aggregation, ROS generation and necrosis/apoptosis-mediated cell death. Since imbalance in the serotonin level is known to predispose diverse pathological conditions including serotonin syndrome, atherosclerosis, diabetes, and Alzheimer's diseases, our results on the formation of cytotoxic nanoassemblies via serotonin oxidation may provide important evidence for understanding the molecular mechanism of serotonin associated complications.