Membrane binding of oligomeric α‐synuclein depends on bilayer charge and packing

Rooijen, Bart van; Claessens, Mireille Maria Anna Elisabeth; Subramaniam, Vinod

doi:10.1016/j.febslet.2008.10.009

Cited by 70 publications

(109 citation statements)

References 29 publications

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“…For simplicity we have only tested the oligomer on 100% anionic lipids, however, it is known that also vesicles with lower levels of anionic lipids can also be disrupted by an isolated αSN oligomer (21,27). Our data increase the likelihood that the oligomer could be cytotoxic in vivo and we have modeled the wreath-shaped oligomeric species that we suggest is responsible for this function.…”

Section: Discussionmentioning

confidence: 99%

“…We identified four species present in detectable amounts in equilibrium throughout the fibrillation process. Monomers and dimers of αSN exist in equilibrium upon dissolution (5,20,21), thus we assign three of the species to monomer, dimer and fibrils and conclude that a fourth species coexists during the fibrillation process. We then used the program OLIGOMER (19).…”

Section: Decomposition Of Saxs Data and Identification Of An On-pathwaymentioning

confidence: 99%

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Low-resolution structure of a vesicle disrupting α-synuclein oligomer that accumulates during fibrillation

Giehm

Svergun

Otzen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

229

264

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One of the major hallmarks of Parkinson disease is aggregation of the protein α-synuclein (αSN). Aggregate cytotoxicity has been linked to an oligomeric species formed at early stages in the aggregation process. Here we follow the fibrillation process of αSN in solution over time using small angle X-ray scattering and resolve four major coexisting species in the fibrillation process, namely monomer, dimer, fibril and an oligomer. By ab initio modeling to fit the data, we obtain a low-resolution structure of a symmetrical and slender αSN fibril in solution, consisting of a repeating unit with a maximal distance of 900 Å and a diameter of ∼180 Å. The same approach shows the oligomer to be shaped like a wreath, with a central channel and with dimensions corresponding to the width of the fibril. The structure, accumulation and decay of this oligomer is consistent with an on-pathway role for the oligomer in the fibrillation process. We propose an oligomer-driven αSN fibril formation mechanism, where the fibril is built from the oligomers. The wreath-shaped structure of the oligomer highlights its potential cytotoxicity by simple membrane permeabilization. This is confirmed by the ability of the purified oligomer to disrupt liposomes. Our results provide the first structural description in solution of a potentially cytotoxic oligomer, which accumulates during the fibrillation of αSN.alpha-synuclein | amyloid | structral nucleus | solution structure P arkinson Disease (PD) is a common neurodegenerative disorder of the brain. Hallmarks of PD are massive death of dopaminergic neurons and formation of intracellular Lewy bodies (LBs). LBs mainly consist of large fibrillar inclusions of α-synuclein (αSN), a 140-residue natively unfolded protein (1). Numerous in vitro studies of αSN fibrillation have shown that fibril formation is a nucleated polymerization and that oligomers form transiently in the lag phase (1-5). Such oligomers, rather than fibrils or monomers, have been suggested to be the neurotoxic species (4, 6), however whether the oligomers are on-or offpathway in fibril formation and whether the cytotoxic species corresponds to the nucleus of fibrillation remain unclear. Neurotoxicity is proposed to arise from a pore-like membrane permeabilization (6) or by destabilization of the membrane allowing nonspecific ion-transport (7). Unambiguous structural information of the cytotoxic species is difficult to obtain due to sample coexistence of different species, sensitivity to sample handling and potential surface-binding artifacts. The morphology of purified oligomers from wildtype and mutant αSN have been studied by atomic force microscopy (AFM) and electron microscopy (EM) (4, 5), but purified oligomers may be structurally and functionally distinct from those in equilibrium with monomers and fibrils. Different conditions can lead to different oligomers (4, 5, 8) with varying ability to disrupt artificial cell membranes (9-12). Ideally, structural studies should be conducted on an unperturbed ensemble of all potential ...

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Section: Discussionmentioning

confidence: 99%

Section: Decomposition Of Saxs Data and Identification Of An On-pathwaymentioning

confidence: 99%

Low-resolution structure of a vesicle disrupting α-synuclein oligomer that accumulates during fibrillation

Giehm

Svergun

Otzen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

229

264

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“…These oligomers have not been chemically modified and on average consist of ϳ30 monomers (31,32), forming a rather compact ␤-sheet core with a disordered outer shell. ␣SN oligomers interact with and perturb membranes by a combination of electrostatic interactions between the N terminus of ␣SN and lipid head groups combined with hydrophobic interactions (33)(34)(35)(36)(37)(38).…”

mentioning

confidence: 99%

How Epigallocatechin Gallate Can Inhibit α-Synuclein Oligomer Toxicity in Vitro

Lorenzen

Nielsen

Yoshimura

et al. 2014

Journal of Biological Chemistry

183

192

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Background: Protein oligomers are implicated as cytotoxic membrane-disrupting agents in neurodegenerative diseases. Results: The small molecule EGCG, which inhibits ␣-synuclein oligomer toxicity, moderately reduces membrane binding and immobilizing the oligomer C-terminal tail. Conclusion:The ␣-synuclein oligomer may disrupt membranes by vesicle destabilization rather than pore formation. Significance: Limited reduction of oligomer membrane affinity may be sufficient to prevent cytotoxicity.

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“…This process dependent on the presence of negatively charged lipids being in a liquid disordered phase, while the headgroup is only of minor importance [35,36]. This behavior, which is comparable to monomeric α-synuclein suggests that mainly electrostatic interactions between the positively charged core of the oligomers and negatively charged lipid headgroups cause membrane binding [37,38].…”

Section: A Gonzalez-horta Et Almentioning

confidence: 83%

Fluorescence as a Tool to Study Lipid-Protein Interactions: The Case of α-Synuclein

González-Horta¹,

Hernández²,

Chávez-Montes³

2013

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During the past 20 years there has been a remarkable growth in the use of fluorescence in the biological sciences. Fluorescence is now a dominant methodology used extensively in biochemistry, biophysics, biotechnology, medical diagnostics, flow cytometry, DNA sequencing and genetic analysis to name a few. It is one of the most powerful methods to study protein folding, dynamics, assembly and interactions as well as membrane structure. α-Synuclein belongs to the class of intrinsically disordered proteins lacking of a well-folded structure under physiological conditions. The conversion of α-synuclein from a soluble monomer to an insoluble fibril may underlie the neurodegeneration associated with Parkinson's disease (PD). Although the exact mechanism of α-synuclein toxicity is still unknown, it has been proposed that disturbs membrane structure, leading to increased membrane permeability and eventual cell death. This review highlights the significant role played by fluorescence techniques in unraveling the nature of interactions between α-synuclein and membranes and its implications in PD.

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Membrane binding of oligomeric α‐synuclein depends on bilayer charge and packing

Cited by 70 publications

References 29 publications

Low-resolution structure of a vesicle disrupting α-synuclein oligomer that accumulates during fibrillation

Low-resolution structure of a vesicle disrupting α-synuclein oligomer that accumulates during fibrillation

How Epigallocatechin Gallate Can Inhibit α-Synuclein Oligomer Toxicity in Vitro

Fluorescence as a Tool to Study Lipid-Protein Interactions: The Case of α-Synuclein

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