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α-synuclein fibril and synaptic vesicle interactions lead to vesicle destruction and increased lipid-associated fibril uptake into iPSC-derived neurons

Published version
Peer-reviewed

Repository DOI


Type

Article

Change log

Authors

Kaminski Schierle, Gabriele S  ORCID logo  https://orcid.org/0000-0002-1843-2202
Stephens, Amberley D  ORCID logo  https://orcid.org/0000-0002-7303-6392
Fernandez Villegas, Ana 
Vanderpoorten, Oliver 

Abstract

Monomeric alpha-synuclein (aSyn) is a well characterised protein that importantly binds to lipids. aSyn monomers assemble into amyloid fibrils which are localised to lipids and organelles in insoluble structures found in Parkinson’s disease patient’s brains. Previous work to address pathological aSyn-lipid interactions has focused on using synthetic lipid membranes, which lack the complexity of physiological lipid membranes. Here, we use physiological membranes in the form of synaptic vesicles (SV) isolated from rodent brain to demonstrate that lipid-associated aSyn fibrils are more easily taken up into iPSC-derived cortical i3Neurons. Lipid-associated aSyn fibril characterisation reveals that SV lipids are an integrated part of the fibrils and while their fibril morphology differs from aSyn fibrils alone, the core fibril structure remains the same, suggesting the lipids lead to the increase in fibril uptake. Furthermore, SV enhance the aggregation rate of aSyn, yet increasing the SV:aSyn ratio causes a reduction in aggregation propensity. We finally show that aSyn fibrils disintegrate SV, whereas aSyn monomers cause clustering of SV using small angle neutron scattering and high-resolution imaging. Disease burden on neurons may be impacted by an increased uptake of lipid-associated aSyn which could enhance stress and pathology, which in turn may have fatal consequences for neurons.

Description

Keywords

Animals, alpha-Synuclein, Synaptic Vesicles, Induced Pluripotent Stem Cells, Neurons, Rodentia, Lipids

Journal Title

Communications Biology

Conference Name

Journal ISSN

2399-3642
2399-3642

Volume Title

6

Publisher

Nature Portfolio
Sponsorship
Medical Research Council (MR/K02292X/1)
Wellcome Trust (065807/Z/01/Z)
Engineering and Physical Sciences Research Council (EP/L015889/1)
Wellcome Trust (203249/Z/16/Z)
Oppenheimer Foundation, Cambridge Trust, and Horizon Europe Program (101064246)