The 3D structure of lipidic fibrils of α-synuclein

Benedikt Frieg, Leif Antonschmidt, Christian Dienemann, James A. Geraets, Eszter E. Najbauer, Dirk Matthes, Bert L. Groot, Loren B. Andreas, Stefan Becker, Christian Griesinger () and Gunnar F. Schröder ()
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Benedikt Frieg: Forschungszentrum Jülich
Leif Antonschmidt: Max Planck Institute for Multidisciplinary Sciences
Christian Dienemann: Max Planck Institute for Multidisciplinary Sciences
James A. Geraets: Forschungszentrum Jülich
Eszter E. Najbauer: Max Planck Institute for Multidisciplinary Sciences
Dirk Matthes: Max Planck Institute for Multidisciplinary Sciences
Bert L. Groot: Max Planck Institute for Multidisciplinary Sciences
Loren B. Andreas: Max Planck Institute for Multidisciplinary Sciences
Stefan Becker: Max Planck Institute for Multidisciplinary Sciences
Christian Griesinger: Max Planck Institute for Multidisciplinary Sciences
Gunnar F. Schröder: Forschungszentrum Jülich

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract α-synuclein misfolding and aggregation into fibrils is a common feature of α-synucleinopathies, such as Parkinson’s disease, in which α-synuclein fibrils are a characteristic hallmark of neuronal inclusions called Lewy bodies. Studies on the composition of Lewy bodies extracted postmortem from brain tissue of Parkinson’s patients revealed that lipids and membranous organelles are also a significant component. Interactions between α-synuclein and lipids have been previously identified as relevant for Parkinson’s disease pathology, however molecular insights into their interactions have remained elusive. Here we present cryo-electron microscopy structures of six α-synuclein fibrils in complex with lipids, revealing specific lipid-fibril interactions. We observe that phospholipids promote an alternative protofilament fold, mediate an unusual arrangement of protofilaments, and fill the central cavities of the fibrils. Together with our previous studies, these structures also indicate a mechanism for fibril-induced lipid extraction, which is likely to be involved in the development of α-synucleinopathies. Specifically, one potential mechanism for the cellular toxicity is the disruption of intracellular vesicles mediated by fibrils and oligomers, and therefore the modulation of these interactions may provide a promising strategy for future therapeutic interventions.

Date: 2022
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DOI: 10.1038/s41467-022-34552-7

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