A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles
α-Synuclein (αS) is a presynaptic protein whose aggregation is associated with Parkinson’s disease (PD). Although the physiological function of αS is still unclear, several lines of evidence indicate that this protein may play a role in the trafficking of synaptic vesicles (SVs) during neurotransmit...
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| Format: | Article |
| Jezik: | English |
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Frontiers Media S.A.
2020-01-01
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| Serija: | Frontiers in Neuroscience |
| Teme: | |
| Online dostop: | https://www.frontiersin.org/article/10.3389/fnins.2020.00018/full |
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| author | Wing K. Man Alfonso De Simone Joseph D. Barritt Michele Vendruscolo Christopher M. Dobson Giuliana Fusco |
| author_facet | Wing K. Man Alfonso De Simone Joseph D. Barritt Michele Vendruscolo Christopher M. Dobson Giuliana Fusco |
| author_sort | Wing K. Man |
| collection | DOAJ |
| description | α-Synuclein (αS) is a presynaptic protein whose aggregation is associated with Parkinson’s disease (PD). Although the physiological function of αS is still unclear, several lines of evidence indicate that this protein may play a role in the trafficking of synaptic vesicles (SVs) during neurotransmitter release, a task associated with its ability to bind SVs and promote their clustering. It is therefore crucial to identify the cellular factors that modulate this process. To address this question, using nuclear magnetic resonance (NMR) spectroscopy we have characterized the role of cholesterol, a major component of the membrane of SVs, in the binding of αS with synaptic-like vesicles. Our results indicate that cholesterol can act as a modulator of the overall affinity of αS for SVs by reducing the local affinity of the region spanning residues 65–97 in the non-amyloid-β component (NAC) of the protein. The increased population of bound states that expose the region 65–97 to the solvent was found to induce stronger vesicle-vesicle interactions by αS. These results provide evidence that cholesterol modulates the clustering of synaptic vesicles induced by (α)S, and supports the role of the disorder-to-order equilibrium of the NAC region in the modulation of the biological properties of the membrane-bound state of αS. |
| first_indexed | 2024-12-23T07:10:00Z |
| format | Article |
| id | doaj.art-c0bb5ca4f8174bba84c38a19eb5eb1c7 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-23T07:10:00Z |
| publishDate | 2020-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-c0bb5ca4f8174bba84c38a19eb5eb1c72022-12-21T17:55:59ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2020-01-011410.3389/fnins.2020.00018511093A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like VesiclesWing K. Man0Alfonso De Simone1Joseph D. Barritt2Michele Vendruscolo3Christopher M. Dobson4Giuliana Fusco5Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Life Sciences, Imperial College London, London, United KingdomDepartment of Life Sciences, Imperial College London, London, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United Kingdomα-Synuclein (αS) is a presynaptic protein whose aggregation is associated with Parkinson’s disease (PD). Although the physiological function of αS is still unclear, several lines of evidence indicate that this protein may play a role in the trafficking of synaptic vesicles (SVs) during neurotransmitter release, a task associated with its ability to bind SVs and promote their clustering. It is therefore crucial to identify the cellular factors that modulate this process. To address this question, using nuclear magnetic resonance (NMR) spectroscopy we have characterized the role of cholesterol, a major component of the membrane of SVs, in the binding of αS with synaptic-like vesicles. Our results indicate that cholesterol can act as a modulator of the overall affinity of αS for SVs by reducing the local affinity of the region spanning residues 65–97 in the non-amyloid-β component (NAC) of the protein. The increased population of bound states that expose the region 65–97 to the solvent was found to induce stronger vesicle-vesicle interactions by αS. These results provide evidence that cholesterol modulates the clustering of synaptic vesicles induced by (α)S, and supports the role of the disorder-to-order equilibrium of the NAC region in the modulation of the biological properties of the membrane-bound state of αS.https://www.frontiersin.org/article/10.3389/fnins.2020.00018/fullα-synucleinsynaptic vesiclesmembrane interactioncholesterolnuclear magnetic resonance |
| spellingShingle | Wing K. Man Alfonso De Simone Joseph D. Barritt Michele Vendruscolo Christopher M. Dobson Giuliana Fusco A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles Frontiers in Neuroscience α-synuclein synaptic vesicles membrane interaction cholesterol nuclear magnetic resonance |
| title | A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles |
| title_full | A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles |
| title_fullStr | A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles |
| title_full_unstemmed | A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles |
| title_short | A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles |
| title_sort | role of cholesterol in modulating the binding of α synuclein to synaptic like vesicles |
| topic | α-synuclein synaptic vesicles membrane interaction cholesterol nuclear magnetic resonance |
| url | https://www.frontiersin.org/article/10.3389/fnins.2020.00018/full |
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