Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism

Limbocker et al. show that trodusquemine, an aminosterol, reduces the cytotoxicity of protein misfolded oligomers by displacing them from cell membranes in the absence of any overt structural/ morphological changes in them. This mechanism appears to be general, as they test it for oligomers of alpha S, A beta and the model protein HypF-N to human neuroblastoma cells. The onset and progression of numerous protein misfolding diseases are associated with the presence of oligomers formed during the aberrant aggregation of several different proteins, including amyloid-beta (A beta) in Alzheimer's disease and alpha-synuclein (alpha S) in Parkinson's disease. These small, soluble aggregates are currently major targets for drug discovery. In this study, we show that trodusquemine, a naturally-occurring aminosterol, markedly reduces the cytotoxicity of alpha S, A beta and HypF-N oligomers to human neuroblastoma cells by displacing the oligomers from cell membranes in the absence of any substantial morphological and structural changes to the oligomers. These results indicate that the reduced toxicity results from a mechanism that is common to oligomers from different proteins, shed light on the origin of the toxicity of the most deleterious species associated with protein aggregation and suggest that aminosterols have the therapeutically-relevant potential to protect cells from the oligomer-induced cytotoxicity associated with numerous protein misfolding diseases.