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bioRxiv · 10.1101/2022.03.02.481946

The 3D structure of lipidic fibrils of α-synuclein

Frieg, B.·Antonschmidt, L.·Dienemann, C.·Geraets, J. A.·Najbauer, E. E.·Matthes, D.·de Groot, B. L.·Andreas, L. B.·Becker, S.·Griesinger, C.·Schroder, G. F.
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Abstract

-synuclein (Syn) is abundant in neurons, but its misfolding and abnormal fibrillization are associated with severe neurodegenerative diseases. Although interactions between Syn and phospholipid membranes are relevant during Syn fibril assembly, insights into the interactions of Syn fibrils with phospholipids have remained elusive. Here, we present six novel polymorphic atomic structures of Syn fibrils aggregated in the presence of phospholipids. The structures reveal that phospholipids favor a novel protofilament fold, mediate an unusual arrangement of protofilaments, and fill the central cavities between the protofilaments. These findings provide a structural rationale for fibril-induced lipid extraction, a mechanism likely to be involved in the development of -synucleinopathies.

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Frieg, B., Antonschmidt, L., Dienemann, C., Geraets, J. A., Najbauer, E. E., Matthes, D., de Groot, B. L., Andreas, L. B., Becker, S., Griesinger, C., Schroder, G. F.. 2022-03-02. The 3D structure of lipidic fibrils of α-synuclein. https://doi.org/10.1101/2022.03.02.481946

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