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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| Language: | English |
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2021.680026/full |
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| author | Ryan Limbocker Ryan Limbocker Roxine Staats Sean Chia Francesco S. Ruggeri Francesco S. Ruggeri Francesco S. Ruggeri Benedetta Mannini Catherine K. Xu Michele Perni Roberta Cascella Alessandra Bigi Liam R. Sasser Natalie R. Block Aidan K. Wright Ryan P. Kreiser Edward T. Custy Georg Meisl Silvia Errico Silvia Errico Johnny Habchi Patrick Flagmeier Tadas Kartanas Jared E. Hollows Lam T. Nguyen Kathleen LeForte Denise Barbut Janet R. Kumita Cristina Cecchi Michael Zasloff Michael Zasloff Tuomas P. J. Knowles Tuomas P. J. Knowles Christopher M. Dobson Fabrizio Chiti Michele Vendruscolo |
| author_facet | Ryan Limbocker Ryan Limbocker Roxine Staats Sean Chia Francesco S. Ruggeri Francesco S. Ruggeri Francesco S. Ruggeri Benedetta Mannini Catherine K. Xu Michele Perni Roberta Cascella Alessandra Bigi Liam R. Sasser Natalie R. Block Aidan K. Wright Ryan P. Kreiser Edward T. Custy Georg Meisl Silvia Errico Silvia Errico Johnny Habchi Patrick Flagmeier Tadas Kartanas Jared E. Hollows Lam T. Nguyen Kathleen LeForte Denise Barbut Janet R. Kumita Cristina Cecchi Michael Zasloff Michael Zasloff Tuomas P. J. Knowles Tuomas P. J. Knowles Christopher M. Dobson Fabrizio Chiti Michele Vendruscolo |
| author_sort | Ryan Limbocker |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-16T13:12:45Z |
| format | Article |
| id | doaj.art-dd03b8d056964d40bab6c08d74df6acb |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-16T13:12:45Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-dd03b8d056964d40bab6c08d74df6acb2022-12-21T22:30:34ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2021-06-011510.3389/fnins.2021.680026680026Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their OligomersRyan Limbocker0Ryan Limbocker1Roxine Staats2Sean Chia3Francesco S. Ruggeri4Francesco S. Ruggeri5Francesco S. Ruggeri6Benedetta Mannini7Catherine K. Xu8Michele Perni9Roberta Cascella10Alessandra Bigi11Liam R. Sasser12Natalie R. Block13Aidan K. Wright14Ryan P. Kreiser15Edward T. Custy16Georg Meisl17Silvia Errico18Silvia Errico19Johnny Habchi20Patrick Flagmeier21Tadas Kartanas22Jared E. Hollows23Lam T. Nguyen24Kathleen LeForte25Denise Barbut26Janet R. Kumita27Cristina Cecchi28Michael Zasloff29Michael Zasloff30Tuomas P. J. Knowles31Tuomas P. J. Knowles32Christopher M. Dobson33Fabrizio Chiti34Michele Vendruscolo35Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry & Life Science, United States Military Academy, West Point, NY, United StatesCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomLaboratory of Organic Chemistry, Wageningen University, Wageningen, NetherlandsLaboratory of Physical Chemistry, Wageningen University, Wageningen, NetherlandsCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomDepartment of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, ItalyDepartment of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, ItalyDepartment of Chemistry & Life Science, United States Military Academy, West Point, NY, United StatesDepartment of Chemistry & Life Science, United States Military Academy, West Point, NY, United StatesDepartment of Chemistry & Life Science, United States Military Academy, West Point, NY, United StatesDepartment of Chemistry & Life Science, United States Military Academy, West Point, NY, United StatesDepartment of Chemistry & Life Science, United States Military Academy, West Point, NY, United StatesCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomDepartment of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, ItalyCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry & Life Science, United States Military Academy, West Point, NY, United StatesDepartment of Chemistry & Life Science, United States Military Academy, West Point, NY, United StatesDepartment of Chemistry & Life Science, United States Military Academy, West Point, NY, United StatesEnterin Inc., Philadelphia, PA, United StatesCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomDepartment of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, ItalyEnterin Inc., Philadelphia, PA, United StatesMedStar Georgetown Transplant Institute, School of Medicine, Georgetown University, Washington, DC, United StatesCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomCavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, United KingdomCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomDepartment of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, ItalyCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United KingdomThe 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.https://www.frontiersin.org/articles/10.3389/fnins.2021.680026/fullprotein misfolding diseasesamyloid-βAlzheimer’s diseaseα-synucleinParkinson’s diseaseoligomers |
| spellingShingle | Ryan Limbocker Ryan Limbocker Roxine Staats Sean Chia Francesco S. Ruggeri Francesco S. Ruggeri Francesco S. Ruggeri Benedetta Mannini Catherine K. Xu Michele Perni Roberta Cascella Alessandra Bigi Liam R. Sasser Natalie R. Block Aidan K. Wright Ryan P. Kreiser Edward T. Custy Georg Meisl Silvia Errico Silvia Errico Johnny Habchi Patrick Flagmeier Tadas Kartanas Jared E. Hollows Lam T. Nguyen Kathleen LeForte Denise Barbut Janet R. Kumita Cristina Cecchi Michael Zasloff Michael Zasloff Tuomas P. J. Knowles Tuomas P. J. Knowles Christopher M. Dobson Fabrizio Chiti Michele Vendruscolo Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers Frontiers in Neuroscience protein misfolding diseases amyloid-β Alzheimer’s disease α-synuclein Parkinson’s disease 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 | protein misfolding diseases amyloid-β Alzheimer’s disease α-synuclein Parkinson’s disease oligomers |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2021.680026/full |
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