Cooperativity of α-Synuclein Binding to Lipid Membranes

Makasewicz, Katarzyna; Wennmalm, Stefan; Stenqvist, Björn; Fornasier, Marco; Andersson, Alexandra; Jönsson, Peter; Linse, Sara; Sparr, Emma

doi:10.1021/acschemneuro.1c00006

Cited by 24 publications

(39 citation statements)

References 37 publications

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“…In all of the protein-containing samples, α-synuclein was added to attain a lipid-to-protein (L/P) ratio of 200. We have previously shown that for the DOPC:DOPS 7:3 system at this L/P virtually all α-synuclein molecules are bound to the membrane Makasewicz et al (2021). We note that there are a few examples of deformed vesicles present in the sample containing only vesicles in MES buffer (Figure 1A,C), which can be explained by that some amount of water may evaporate from the thin liquid 100 film during cryo-TEM sample deposition.…”

Section: α-Synuclein Induces Deformation Of Small Unilamellar Vesiclesmentioning

confidence: 69%

α-Synuclein-induced deformation of small unilamellar vesicles

et al. 2022

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α-synuclein is a small neuronal protein that reversibly associates with lipid membranes. The membrane interactions are believed to be central to the healthy function of this protein involved in synaptic plasticity and neurotransmitter release. α-synuclein has been speculated to induce vesicle fusion as well as fission, processes which are analogous to each other but proceed in different directions and involve different driving forces. In the current work, we analyze α-synuclein-induced small unilamellar vesicle deformation from a thermodynamics point of view. We show that the structures interpreted in the literature as fusion intermediates are in fact a stable deformed state and no fusion nor vesicle clustering occurs. We speculate on the driving force for the observed deformation and put forward a hypothesis that α-synuclein self-assembly on the lipid membrane precedes and induces membrane remodeling.

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Section: α-Synuclein Induces Deformation Of Small Unilamellar Vesiclesmentioning

confidence: 69%

α-Synuclein-induced deformation of small unilamellar vesicles

et al. 2022

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“…Here, the lipid-to-protein ratio, L/P = 5, is relatively low, and we expect to have a significant fraction of free, nonadsorbed aSyn molecules. 17 The excess of the free protein allows for the fibril formation to take place, as discussed in Galvagnion et al 23 …”

Section: Resultsmentioning

confidence: 99%

α-Synuclein Interaction with Lipid Bilayer Discs

et al. 2022

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α-Synuclein (aSyn) is a 140 residue long protein present in presynaptic termini of nerve cells. The protein is associated with Parkinson’s disease, in which case it has been found to self-assemble into long amyloid fibrils forming intracellular inclusions that are also rich in lipids. Furthermore, its synaptic function is proposed to involve interaction with lipid membranes, and hence, it is of interest to understand aSyn–lipid membrane interactions in detail. In this paper we report on the interaction of aSyn with model membranes in the form of lipid bilayer discs. Using a combination of cryogenic transmission electron microscopy and small-angle neutron scattering, we show that circular discs undergo a significant shape transition after the adsorption of aSyn. When aSyn self-assembles into fibrils, aSyn molecules desorb from the bilayer discs, allowing them to recover to their original shape. Interestingly, the desorption process has an all-or-none character, resulting in a binary coexistence of circular bilayer discs with no adsorbed aSyn and deformed bilayer discs having a maximum amount of adsorbed protein. The observed coexistence is consistent with the recent finding of cooperative aSyn adsorption to anionic lipid bilayers.

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“…It has been shown that monomeric αS adsorbs to anionic lipid membranes (Jao et al, 2004;Pfefferkorn et al, 2012;Hellstrand et al, 2013a;Fusco et al, 2014), and that the membrane under some conditions can have a catalytic effect on fibril formation (Galvagnion et al, 2015;Grey et al, 2015;Galvagnion, 2017;Gaspar et al, 2019). Interestingly, this adsorption appears to be a strongly cooperative process (Makasewicz et al, 2021). Several studies, performed with different systems, have also indicated that αS and lipids may form coaggregates (Reynolds et al, 2011;Hellstrand et al, 2013b;van Maarschalkerweerd et al, 2014;Galvagnion et al, 2019;Gaspar et al, 2021).…”

Section: Introductionmentioning

confidence: 95%

“…In vivo, the fibril formation process occurs in a highly lipid-rich environment, and Lewy bodies are known to contain significant amounts of lipid (Shults, 2006;Stefanis, 2012;Araki et al, 2019;Fanning et al, 2020;Lashuel, 2020). These facts have motivated studies of αS-lipid interactions, involving both monomeric (Fusco et al, 2014;van Maarschalkerweerd et al, 2014;Fusco et al, 2016;Hannestad et al, 2020;Makasewicz et al, 2021), andfibrillar αS (van Rooijen et al, 2009;Hellstrand et al, 2013b;Galvagnion et al, 2019;Gaspar et al, 2021). It has been shown that monomeric αS adsorbs to anionic lipid membranes (Jao et al, 2004;Pfefferkorn et al, 2012;Hellstrand et al, 2013a;Fusco et al, 2014), and that the membrane under some conditions can have a catalytic effect on fibril formation (Galvagnion et al, 2015;Grey et al, 2015;Galvagnion, 2017;Gaspar et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Comparing α-Synuclein Fibrils Formed in the Absence and Presence of a Model Lipid Membrane: A Small and Wide-Angle X-Ray Scattering Study

Dubackic¹,

Linse²,

Sparr³

et al. 2022

Front. Soft. Matter

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Amyloid fibrils are associated with a number of different neurodegenerative diseases. Detailed knowledge of the fibril structure will be of importance in the search of therapy and may guide experiments to understand amyloid formation. In this paper we investigate the morphology of α-synuclein amyloid fibrils, associated with Parkinson’s disease, formed under different conditions. In particular, we study, by means of small and wide-angle X-ray scattering, whether the presence of model lipid membranes affect the overall structure of the fibrils formed, motivated by the fact that amyloid fibrils in vivo are formed in a highly lipid-rich environment. Comparing fibrils formed in the presence of lipid with fibrils formed in their absence, show that the presence of lipids has no detectable effect on the fibril cross-section radius and that the characteristic β-strand repeat distance of 4.7 Å of the extended intermolecular β-sheets remains unaffected. We also show that the observed fibril radius is consistent with a fibril structure composed of two protofilaments. This indicates overall that the particular fibril structure, with their stacks of two-dimensionally folded α-synuclein molecules, represent a deep free energy minimum, not largely affected by the co-aggregation with lipids.

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Cooperativity of α-Synuclein Binding to Lipid Membranes

Cited by 24 publications

References 37 publications

α-Synuclein-induced deformation of small unilamellar vesicles

α-Synuclein-induced deformation of small unilamellar vesicles

α-Synuclein Interaction with Lipid Bilayer Discs

Comparing α-Synuclein Fibrils Formed in the Absence and Presence of a Model Lipid Membrane: A Small and Wide-Angle X-Ray Scattering Study

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