Abstract
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-β (Aβ) in Alzheimer’s disease and α-synuclein (αS) 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 αS, Aβ 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.
Highlights
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-β (Aβ) in Alzheimer’s disease and α-synuclein in Parkinson’s disease
We began our cellular investigations by determining the ability of toxic type A HypF protein from E. coli (HypF-N) oligomers[8] (6 μM, monomer equivalents), typically having a height of 2–6 nm, as determined with atomic force microscopy (AFM)[8], to reduce the viability of SHSY5Y cells
There has been a considerable focus in recent years on the soluble oligomers formed during protein aggregation, leading to the development of methods to stabilize, isolate, and characterize such species to probe the origins of their cellular toxicity and of their ability to induce synaptic dysfunction[4]
Summary
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-β (Aβ) in Alzheimer’s disease and α-synuclein (αS) in Parkinson’s disease These small, soluble aggregates are currently major targets for drug discovery. The application of a highly sensitive kinetic assay to characterize the aggregation behavior of the 42-residue form of the amyloid-β protein (Aβ42)[12,13,14] has suggested the possibility of reducing the toxicity inherent to protein aggregation by targeting the generation of oligomers[15] This methodology has enabled the detailed evaluation of compounds, including molecular chaperones, antibodies, and small molecules, for their abilities to inhibit the aggregation process of Aβ42 in a specific manner so that the overall concentration of oligomers produced during the process is reduced. Similar strategies have been employed to identify species that inhibit oligomer formation by αS, in particular by targeting the microscopic step of fibril amplification[20,21,22]
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