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Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers

The aberrant aggregation of proteins is a key molecular event in the development and progression of a wide range of neurodegenerative disorders. We have shown previously that squalamine and trodusquemine, two natural products in the aminosterol class, can modulate the aggregation of the amyloid-β pe...

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Autores principales: Limbocker, Ryan, Staats, Roxine, Chia, Sean, Ruggeri, Francesco S., Mannini, Benedetta, Xu, Catherine K., Perni, Michele, Cascella, Roberta, Bigi, Alessandra, Sasser, Liam R., Block, Natalie R., Wright, Aidan K., Kreiser, Ryan P., Custy, Edward T., Meisl, Georg, Errico, Silvia, Habchi, Johnny, Flagmeier, Patrick, Kartanas, Tadas, Hollows, Jared E., Nguyen, Lam T., LeForte, Kathleen, Barbut, Denise, Kumita, Janet R., Cecchi, Cristina, Zasloff, Michael, Knowles, Tuomas P. J., Dobson, Christopher M., Chiti, Fabrizio, Vendruscolo, Michele
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249941/
https://www.ncbi.nlm.nih.gov/pubmed/34220435
http://dx.doi.org/10.3389/fnins.2021.680026
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author Limbocker, Ryan
Staats, Roxine
Chia, Sean
Ruggeri, Francesco S.
Mannini, Benedetta
Xu, Catherine K.
Perni, Michele
Cascella, Roberta
Bigi, Alessandra
Sasser, Liam R.
Block, Natalie R.
Wright, Aidan K.
Kreiser, Ryan P.
Custy, Edward T.
Meisl, Georg
Errico, Silvia
Habchi, Johnny
Flagmeier, Patrick
Kartanas, Tadas
Hollows, Jared E.
Nguyen, Lam T.
LeForte, Kathleen
Barbut, Denise
Kumita, Janet R.
Cecchi, Cristina
Zasloff, Michael
Knowles, Tuomas P. J.
Dobson, Christopher M.
Chiti, Fabrizio
Vendruscolo, Michele
author_facet Limbocker, Ryan
Staats, Roxine
Chia, Sean
Ruggeri, Francesco S.
Mannini, Benedetta
Xu, Catherine K.
Perni, Michele
Cascella, Roberta
Bigi, Alessandra
Sasser, Liam R.
Block, Natalie R.
Wright, Aidan K.
Kreiser, Ryan P.
Custy, Edward T.
Meisl, Georg
Errico, Silvia
Habchi, Johnny
Flagmeier, Patrick
Kartanas, Tadas
Hollows, Jared E.
Nguyen, Lam T.
LeForte, Kathleen
Barbut, Denise
Kumita, Janet R.
Cecchi, Cristina
Zasloff, Michael
Knowles, Tuomas P. J.
Dobson, Christopher M.
Chiti, Fabrizio
Vendruscolo, Michele
author_sort Limbocker, Ryan
collection PubMed
description The aberrant aggregation of proteins is a key molecular event in the development and progression of a wide range of neurodegenerative disorders. We have shown previously that squalamine and trodusquemine, two natural products in the aminosterol class, can modulate the aggregation of the amyloid-β peptide (Aβ) and of α-synuclein (αS), which are associated with Alzheimer’s and Parkinson’s diseases. In this work, we expand our previous analyses to two squalamine derivatives, des-squalamine and α-squalamine, obtaining further insights into the mechanism by which aminosterols modulate Aβ and αS aggregation. We then characterize the ability of these small molecules to alter the physicochemical properties of stabilized oligomeric species in vitro and to suppress the toxicity of these aggregates to varying degrees toward human neuroblastoma cells. We found that, despite the fact that these aminosterols exert opposing effects on Aβ and αS aggregation under the conditions that we tested, the modifications that they induced to the toxicity of oligomers were similar. Our results indicate that the suppression of toxicity is mediated by the displacement of toxic oligomeric species from cellular membranes by the aminosterols. This study, thus, provides evidence that aminosterols could be rationally optimized in drug discovery programs to target oligomer toxicity in Alzheimer’s and Parkinson’s diseases.
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spelling pubmed-82499412021-07-03 Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers Limbocker, Ryan Staats, Roxine Chia, Sean Ruggeri, Francesco S. Mannini, Benedetta Xu, Catherine K. Perni, Michele Cascella, Roberta Bigi, Alessandra Sasser, Liam R. Block, Natalie R. Wright, Aidan K. Kreiser, Ryan P. Custy, Edward T. Meisl, Georg Errico, Silvia Habchi, Johnny Flagmeier, Patrick Kartanas, Tadas Hollows, Jared E. Nguyen, Lam T. LeForte, Kathleen Barbut, Denise Kumita, Janet R. Cecchi, Cristina Zasloff, Michael Knowles, Tuomas P. J. Dobson, Christopher M. Chiti, Fabrizio Vendruscolo, Michele Front Neurosci Neuroscience The aberrant aggregation of proteins is a key molecular event in the development and progression of a wide range of neurodegenerative disorders. We have shown previously that squalamine and trodusquemine, two natural products in the aminosterol class, can modulate the aggregation of the amyloid-β peptide (Aβ) and of α-synuclein (αS), which are associated with Alzheimer’s and Parkinson’s diseases. In this work, we expand our previous analyses to two squalamine derivatives, des-squalamine and α-squalamine, obtaining further insights into the mechanism by which aminosterols modulate Aβ and αS aggregation. We then characterize the ability of these small molecules to alter the physicochemical properties of stabilized oligomeric species in vitro and to suppress the toxicity of these aggregates to varying degrees toward human neuroblastoma cells. We found that, despite the fact that these aminosterols exert opposing effects on Aβ and αS aggregation under the conditions that we tested, the modifications that they induced to the toxicity of oligomers were similar. Our results indicate that the suppression of toxicity is mediated by the displacement of toxic oligomeric species from cellular membranes by the aminosterols. This study, thus, provides evidence that aminosterols could be rationally optimized in drug discovery programs to target oligomer toxicity in Alzheimer’s and Parkinson’s diseases. Frontiers Media S.A. 2021-06-18 /pmc/articles/PMC8249941/ /pubmed/34220435 http://dx.doi.org/10.3389/fnins.2021.680026 Text en Copyright © 2021 Limbocker, Staats, Chia, Ruggeri, Mannini, Xu, Perni, Cascella, Bigi, Sasser, Block, Wright, Kreiser, Custy, Meisl, Errico, Habchi, Flagmeier, Kartanas, Hollows, Nguyen, LeForte, Barbut, Kumita, Cecchi, Zasloff, Knowles, Dobson, Chiti and Vendruscolo. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Limbocker, Ryan
Staats, Roxine
Chia, Sean
Ruggeri, Francesco S.
Mannini, Benedetta
Xu, Catherine K.
Perni, Michele
Cascella, Roberta
Bigi, Alessandra
Sasser, Liam R.
Block, Natalie R.
Wright, Aidan K.
Kreiser, Ryan P.
Custy, Edward T.
Meisl, Georg
Errico, Silvia
Habchi, Johnny
Flagmeier, Patrick
Kartanas, Tadas
Hollows, Jared E.
Nguyen, Lam T.
LeForte, Kathleen
Barbut, Denise
Kumita, Janet R.
Cecchi, Cristina
Zasloff, Michael
Knowles, Tuomas P. J.
Dobson, Christopher M.
Chiti, Fabrizio
Vendruscolo, Michele
Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers
title Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers
title_full Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers
title_fullStr Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers
title_full_unstemmed Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers
title_short Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers
title_sort squalamine and its derivatives modulate the aggregation of amyloid-β and α-synuclein and suppress the toxicity of their oligomers
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249941/
https://www.ncbi.nlm.nih.gov/pubmed/34220435
http://dx.doi.org/10.3389/fnins.2021.680026
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