Single-vesicle imaging reveals lipid-selective and stepwise membrane disruption by monomeric α-synuclein

Hannestad, Jonas,1981Chalmers tekniska högskola,Chalmers University of Technology (författare)

The interaction of the neuronal protein α-synuclein with lipid membranes appears crucial in the context of Parkinson's disease, but the underlying mechanistic details, including the roles of different lipids in pathogenic protein aggregation and membrane disruption, remain elusive. Here, we used single-vesicle resolution fluorescence and label-free scattering microscopy to investigate the interaction kinetics of monomeric α-synuclein with surface-tethered vesicles composed of different negatively charged lipids. Supported by a theoretical model to account for structural changes in scattering properties of surface-tethered lipid vesicles, the data demonstrate stepwise vesicle disruption and asymmetric membrane deformation upon α-synuclein binding to phosphatidylglycerol vesicles at protein concentrations down to 10 nM (∼100 proteins per vesicle). In contrast, phosphatidylserine vesicles were only marginally affected. These insights into structural consequences of α-synuclein interaction with lipid vesicles highlight the contrasting roles of different anionic lipids, which may be of mechanistic relevance for both normal protein function (e.g., synaptic vesicle binding) and dysfunction (e.g., mitochondrial membrane interaction).

Rocha, Sandra,1975Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)rochas (författare)
Agnarsson, Björn,1977Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)bjornag (författare)
Zhdanov, Vladimir,1952Russian Academy of Sciences,Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)zhdanov (författare)
Wittung Stafshede, Pernilla,1968Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)perwit (författare)
Höök, Fredrik,1966Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)fredrikh (författare)
Chalmers tekniska högskolaRussian Academy of Sciences (creator_code:org_t)

Ingår i:Proceedings of the National Academy of Sciences of the United States of America: Proceedings of the National Academy of Sciences117:25, s. 14178-141860027-84241091-6490

Av författaren/redakt...: Hannestad, Jonas ...; Rocha, Sandra, 1 ...; Agnarsson, Björn ...; Zhdanov, Vladimi ...; Wittung Stafshed ...; Höök, Fredrik, 1 ...

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