Lipidic folding pathway of α-Synuclein via a toxic oligomer
Abstract Aggregation intermediates play a pivotal role in the assembly of amyloid fibrils, which are central to the pathogenesis of neurodegenerative diseases. The structures of filamentous intermediates and mature fibrils are now efficiently determined by single-particle cryo-electron microscopy. B...
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| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55849-3 |
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| author | Vrinda Sant Dirk Matthes Hisham Mazal Leif Antonschmidt Franz Wieser Kumar T. Movellan Kai Xue Evgeny Nimerovsky Marianna Stampolaki Magdeline Nathan Dietmar Riedel Stefan Becker Vahid Sandoghdar Bert L. de Groot Christian Griesinger Loren B. Andreas |
| author_facet | Vrinda Sant Dirk Matthes Hisham Mazal Leif Antonschmidt Franz Wieser Kumar T. Movellan Kai Xue Evgeny Nimerovsky Marianna Stampolaki Magdeline Nathan Dietmar Riedel Stefan Becker Vahid Sandoghdar Bert L. de Groot Christian Griesinger Loren B. Andreas |
| author_sort | Vrinda Sant |
| collection | DOAJ |
| description | Abstract Aggregation intermediates play a pivotal role in the assembly of amyloid fibrils, which are central to the pathogenesis of neurodegenerative diseases. The structures of filamentous intermediates and mature fibrils are now efficiently determined by single-particle cryo-electron microscopy. By contrast, smaller pre-fibrillar α-Synuclein (αS) oligomers, crucial for initiating amyloidogenesis, remain largely uncharacterized. We report an atomic-resolution structural characterization of a toxic pre-fibrillar aggregation intermediate (I1) on pathway to the formation of lipidic fibrils, which incorporate lipid molecules on protofilament surfaces during fibril growth on membranes. Super-resolution microscopy reveals a tetrameric state, providing insights into the early oligomeric assembly. Time resolved nuclear magnetic resonance (NMR) measurements uncover a structural reorganization essential for the transition of I1 to mature lipidic L2 fibrils. The reorganization involves the transformation of anti-parallel β-strands during the pre-fibrillar I1 state into a β-arc characteristic of amyloid fibrils. This structural reconfiguration occurs in a conserved structural kernel shared by a vast number of αS-fibril polymorphs including extracted fibrils from Parkinson’s and Lewy Body Dementia patients. Consistent with reports of anti-parallel β-strands being a defining feature of toxic αS pre-fibrillar intermediates, I1 impacts viability of neuroblasts and disrupts cell membranes, resulting in an increased calcium influx. Our results integrate the occurrence of anti-parallel β-strands as salient features of toxic oligomers with their significant role in the amyloid fibril assembly pathway. These structural insights have implications for the development of therapies and biomarkers. |
| format | Article |
| id | doaj-art-d4bd70c5c1a24f03bdfefd37f570651a |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d4bd70c5c1a24f03bdfefd37f570651a2025-01-19T12:31:13ZengNature PortfolioNature Communications2041-17232025-01-0116111410.1038/s41467-025-55849-3Lipidic folding pathway of α-Synuclein via a toxic oligomerVrinda Sant0Dirk Matthes1Hisham Mazal2Leif Antonschmidt3Franz Wieser4Kumar T. Movellan5Kai Xue6Evgeny Nimerovsky7Marianna Stampolaki8Magdeline Nathan9Dietmar Riedel10Stefan Becker11Vahid Sandoghdar12Bert L. de Groot13Christian Griesinger14Loren B. Andreas15NMR Based Structural Biology, Max Planck Institute for Multidisciplinary SciencesDepartment of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary SciencesMax Planck Institute for Science of LightNMR Based Structural Biology, Max Planck Institute for Multidisciplinary SciencesMax Planck Institute for Science of LightNMR Based Structural Biology, Max Planck Institute for Multidisciplinary SciencesNMR Based Structural Biology, Max Planck Institute for Multidisciplinary SciencesNMR Based Structural Biology, Max Planck Institute for Multidisciplinary SciencesNMR Based Structural Biology, Max Planck Institute for Multidisciplinary SciencesNMR Based Structural Biology, Max Planck Institute for Multidisciplinary SciencesFacility for Electron Microscopy, Max Planck Institute for Multidisciplinary SciencesNMR Based Structural Biology, Max Planck Institute for Multidisciplinary SciencesMax Planck Institute for Science of LightDepartment of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary SciencesNMR Based Structural Biology, Max Planck Institute for Multidisciplinary SciencesNMR Based Structural Biology, Max Planck Institute for Multidisciplinary SciencesAbstract Aggregation intermediates play a pivotal role in the assembly of amyloid fibrils, which are central to the pathogenesis of neurodegenerative diseases. The structures of filamentous intermediates and mature fibrils are now efficiently determined by single-particle cryo-electron microscopy. By contrast, smaller pre-fibrillar α-Synuclein (αS) oligomers, crucial for initiating amyloidogenesis, remain largely uncharacterized. We report an atomic-resolution structural characterization of a toxic pre-fibrillar aggregation intermediate (I1) on pathway to the formation of lipidic fibrils, which incorporate lipid molecules on protofilament surfaces during fibril growth on membranes. Super-resolution microscopy reveals a tetrameric state, providing insights into the early oligomeric assembly. Time resolved nuclear magnetic resonance (NMR) measurements uncover a structural reorganization essential for the transition of I1 to mature lipidic L2 fibrils. The reorganization involves the transformation of anti-parallel β-strands during the pre-fibrillar I1 state into a β-arc characteristic of amyloid fibrils. This structural reconfiguration occurs in a conserved structural kernel shared by a vast number of αS-fibril polymorphs including extracted fibrils from Parkinson’s and Lewy Body Dementia patients. Consistent with reports of anti-parallel β-strands being a defining feature of toxic αS pre-fibrillar intermediates, I1 impacts viability of neuroblasts and disrupts cell membranes, resulting in an increased calcium influx. Our results integrate the occurrence of anti-parallel β-strands as salient features of toxic oligomers with their significant role in the amyloid fibril assembly pathway. These structural insights have implications for the development of therapies and biomarkers.https://doi.org/10.1038/s41467-025-55849-3 |
| spellingShingle | Vrinda Sant Dirk Matthes Hisham Mazal Leif Antonschmidt Franz Wieser Kumar T. Movellan Kai Xue Evgeny Nimerovsky Marianna Stampolaki Magdeline Nathan Dietmar Riedel Stefan Becker Vahid Sandoghdar Bert L. de Groot Christian Griesinger Loren B. Andreas Lipidic folding pathway of α-Synuclein via a toxic oligomer Nature Communications |
| title | Lipidic folding pathway of α-Synuclein via a toxic oligomer |
| title_full | Lipidic folding pathway of α-Synuclein via a toxic oligomer |
| title_fullStr | Lipidic folding pathway of α-Synuclein via a toxic oligomer |
| title_full_unstemmed | Lipidic folding pathway of α-Synuclein via a toxic oligomer |
| title_short | Lipidic folding pathway of α-Synuclein via a toxic oligomer |
| title_sort | lipidic folding pathway of α synuclein via a toxic oligomer |
| url | https://doi.org/10.1038/s41467-025-55849-3 |
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