Lipidic folding pathway of α-Synuclein via a toxic oligomer

Aggregation intermediates play a pivotal role in the assembly of amyloid fibrils, which are central to the pathogenesis of neurodegenerative diseases ^1,2 . The structures of filamentous intermediates ³ and mature fibrils ⁴ 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. 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 ⁶ , 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 unique features of toxic oligomers ^7-9 with their significant role in the amyloid fibril assembly pathway. These structural insights have implications for the development of therapies and biomarkers.