1. Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism.
- Author
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Limbocker R, Mannini B, Ruggeri FS, Cascella R, Xu CK, Perni M, Chia S, Chen SW, Habchi J, Bigi A, Kreiser RP, Wright AK, Albright JA, Kartanas T, Kumita JR, Cremades N, Zasloff M, Cecchi C, Knowles TPJ, Chiti F, Vendruscolo M, and Dobson CM
- Subjects
- Amyloid beta-Peptides chemistry, Amyloid beta-Peptides toxicity, Biophysical Phenomena drug effects, Carboxyl and Carbamoyl Transferases chemistry, Carboxyl and Carbamoyl Transferases toxicity, Cell Death drug effects, Cell Line, Tumor, Cell Membrane drug effects, Escherichia coli Proteins chemistry, Escherichia coli Proteins toxicity, Humans, Spermine pharmacology, alpha-Synuclein chemistry, alpha-Synuclein toxicity, Cell Membrane metabolism, Cholestanes pharmacology, Protein Folding drug effects, Protein Multimerization drug effects, Spermine analogs & derivatives
- 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.
- Published
- 2020
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