Lipidic folding pathway of α-Synuclein via a toxic oligomer

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. Groot (), Christian Griesinger () and Loren B. Andreas ()
Additional contact information
Vrinda Sant: Max Planck Institute for Multidisciplinary Sciences
Dirk Matthes: Max Planck Institute for Multidisciplinary Sciences
Hisham Mazal: Max Planck Institute for Science of Light
Leif Antonschmidt: Max Planck Institute for Multidisciplinary Sciences
Franz Wieser: Max Planck Institute for Science of Light
Kumar T. Movellan: Max Planck Institute for Multidisciplinary Sciences
Kai Xue: Max Planck Institute for Multidisciplinary Sciences
Evgeny Nimerovsky: Max Planck Institute for Multidisciplinary Sciences
Marianna Stampolaki: Max Planck Institute for Multidisciplinary Sciences
Magdeline Nathan: Max Planck Institute for Multidisciplinary Sciences
Dietmar Riedel: Max Planck Institute for Multidisciplinary Sciences
Stefan Becker: Max Planck Institute for Multidisciplinary Sciences
Vahid Sandoghdar: Max Planck Institute for Science of Light
Bert L. Groot: Max Planck Institute for Multidisciplinary Sciences
Christian Griesinger: Max Planck Institute for Multidisciplinary Sciences
Loren B. Andreas: Max Planck Institute for Multidisciplinary Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-55849-3

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