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

Limbocker, R. ; Mannini, B. ; Ruggeri, F.S. ; Cascella, R. ; Xu, C.K. ; Perni, M. ; Chia, S. ; Chen, S.W. ; Habchi, J. ; Bigi, A. ; Kreiser, R.P. ; Wright, A.K. ; Albright, J.A. ; Kartanas, T. ; Kumita, J.R. ; Cremades, N. (Universidad de Zaragoza) ; Zasloff, M. ; Cecchi, C. ; Knowles, T.P.J. ; Chiti, F. ; Vendruscolo, M. ; Dobson, C.M.

Resumen: 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-ß (Aß) in Alzheimer’s disease and a-synuclein (aS) 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 aS, Aß 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.

Idioma: Inglés

DOI: 10.1038/s42003-020-01140-8

Año: 2020

Publicado en: Communications Biology 3, 1 (2020), 435 1-10
ISSN: 2399-3642

Factor impacto JCR: 6.268 (2020)

Categ. JCR: BIOLOGY rank: 8 / 93 = 0.086 (2020) - Q1 - T1

Factor impacto SCIMAGO: 2.811 - Agricultural and Biological Sciences (miscellaneous) (Q1) - Medicine (miscellaneous) (Q1) - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1)

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)