Lipidic folding pathway of α-Synuclein via a toxic oligomer

Authors

Griesinger C, Sant V, Matthes D, Mazal H, Anstonschmidt L, Wieser F, Movellan, Xue K, Nimerovsky E, Stampolaki M, Nathan M, Riedel D, Becker S, Sandoghdar V, de Groot B, Andreas L

Journal

Research Square

Citation

Research Square 2024. 4 Jun 2024.

Abstract

Aggregation intermediates play a pivotal role in the assembly of amyloid fibrils, which are central to the pathogenesis of neurodegenerative diseases1,2. The structures of filamentous intermediates³ and mature fibrils⁴ 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 intermediates⁶, 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 oligomers⁷⁻⁹ with their significant role in the amyloid fibril assembly pathway. These structural insights have implications for the development of therapies and biomarkers.

DOI

10.21203/rs.3.rs-4437173