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

Published version
Peer-reviewed

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Authors

Limbocker, Ryan 
Ruggeri, Francesco S.  ORCID logo  https://orcid.org/0000-0002-1232-1907
Xu, Catherine K. 

Abstract

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.

Description

Funder: Listed in manuscript for all authors.

Keywords

Article, /631/57, /631/92, article

Journal Title

Communications Biology

Conference Name

Journal ISSN

2399-3642

Volume Title

3

Publisher

Nature Publishing Group UK