Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783717007014756352 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8249941 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT limbockerryan squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT staatsroxine squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT chiasean squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT ruggerifrancescos squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT manninibenedetta squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT xucatherinek squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT pernimichele squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT cascellaroberta squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT bigialessandra squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT sasserliamr squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT blocknatalier squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT wrightaidank squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT kreiserryanp squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT custyedwardt squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT meislgeorg squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT erricosilvia squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT habchijohnny squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT flagmeierpatrick squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT kartanastadas squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT hollowsjarede squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT nguyenlamt squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT lefortekathleen squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT barbutdenise squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT kumitajanetr squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT cecchicristina squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT zasloffmichael squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT knowlestuomaspj squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT dobsonchristopherm squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT chitifabrizio squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers AT vendruscolomichele squalamineanditsderivativesmodulatetheaggregationofamyloidbandasynucleinandsuppressthetoxicityoftheiroligomers |