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α-synuclein fibril and synaptic vesicle interactions lead to vesicle destruction and increased uptake into neurons

View ORCID ProfileAmberley D. Stephens, View ORCID ProfileAna Fernandez Villegas, View ORCID ProfileChyi Wei Chung, View ORCID ProfileOliver Vanderpoorten, Dorothea Pinotsi, View ORCID ProfileIoanna Mela, Edward Ward, View ORCID ProfileThomas M. McCoy, View ORCID ProfileRobert Cubitt, View ORCID ProfileAlexander F. Routh, View ORCID ProfileClemens F. Kaminski, View ORCID ProfileGabriele S. Kaminski Schierle
doi: https://doi.org/10.1101/2022.10.04.510646
Amberley D. Stephens
1Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
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  • For correspondence: asd.stephens@gmail.com gsk20@cam.ac.uk
Ana Fernandez Villegas
1Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
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Chyi Wei Chung
1Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
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Oliver Vanderpoorten
1Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
2Department of Physics and Technology, UiT The Arctic University of Norway, Tromsø, Norway
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Dorothea Pinotsi
3Scientific Center for Optical and Electron Microscopy, ETH Zürich, Zürich, Switzerland
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Ioanna Mela
1Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
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Edward Ward
1Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
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Thomas M. McCoy
1Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
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Robert Cubitt
4Institut Laue Langevin, Grenoble, France
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Alexander F. Routh
1Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
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Clemens F. Kaminski
1Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
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Gabriele S. Kaminski Schierle
1Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
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  • For correspondence: asd.stephens@gmail.com gsk20@cam.ac.uk
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Abstract

Monomeric alpha-synuclein (aSyn) is a well characterised as a lipid binding protein. aSyn is known to form amyloid fibrils which are also localised with lipids and organelles in so called Lewy bodies, insoluble structures found in Parkinson’s disease patient’s brains. It is still unclear under which conditions the aSyn-lipid interaction can start to become pathological. Previous work to address pathological interactions has focused on using synthetic lipid membranes, which lack the complexity of physiological lipid membranes which not only have a more complex lipid composition, but also contain lipid interacting proteins. Here, we investigate how either monomeric or fibrillar aSyn interact with physiological synaptic vesicles (SV) isolated from rodent brain. Using small angle neutron scattering and high-resolution imaging we observe that aSyn fibrils disintegrate SV, whereas aSyn monomers cause clustering of SV. Furthermore, SV enhance the aggregation rate of aSyn, however increasing the SV:aSyn ratio causes a reduction in aggregation propensity. SV lipids appear as an integrated part of aSyn fibrils and while the fibril morphology differs to aSyn fibrils alone, the core fibril structure remains the same. We finally demonstrate that lipid-associated aSyn fibrils are more easily taken up into cortical i3Neurons derived from induced pluripotent stem cells. Our study sheds light on differences between interactions of aSyn with synthetic lipid vesicles and physiological SV. We show how aSyn fibrils may enhance pathology by disintegrating SV, which in turn may have fatal consequences for neurons. Furthermore, disease burden may additionally be impacted by an increased uptake of lipid-associated aSyn by neurons, leading to more SV damage and enhancing aSyn aggregation.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 06, 2022.
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α-synuclein fibril and synaptic vesicle interactions lead to vesicle destruction and increased uptake into neurons
Amberley D. Stephens, Ana Fernandez Villegas, Chyi Wei Chung, Oliver Vanderpoorten, Dorothea Pinotsi, Ioanna Mela, Edward Ward, Thomas M. McCoy, Robert Cubitt, Alexander F. Routh, Clemens F. Kaminski, Gabriele S. Kaminski Schierle
bioRxiv 2022.10.04.510646; doi: https://doi.org/10.1101/2022.10.04.510646
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α-synuclein fibril and synaptic vesicle interactions lead to vesicle destruction and increased uptake into neurons
Amberley D. Stephens, Ana Fernandez Villegas, Chyi Wei Chung, Oliver Vanderpoorten, Dorothea Pinotsi, Ioanna Mela, Edward Ward, Thomas M. McCoy, Robert Cubitt, Alexander F. Routh, Clemens F. Kaminski, Gabriele S. Kaminski Schierle
bioRxiv 2022.10.04.510646; doi: https://doi.org/10.1101/2022.10.04.510646

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