Optical Structural Analysis of Individual α‐Synuclein Oligomers

Varela, Juan A.; Rodrigues, Margarida; Dey, Arghya; Flagmeier, Patrick; Gandhi, Sonia; Dobson, Christopher M.; Klenerman, David; Lee, Steven Frank

doi:10.1002/anie.201710779

Cited by 43 publications

(45 citation statements)

References 27 publications

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“…For the membrane permeabilization assay, vesicles are prepared as previously described [ 26 ]. Using this assay, it has been previously shown α-synuclein oligomers disrupt and permeabilise membranes [ 27 , 28 ]. In brief, vesicles are synthesized using Phospholipids 16:0–18:1 PC and biotinylated lipids 18:1–12:0 Biotin PC (100:1) using freeze thaw method and mean diameter is 200 nm.…”

Section: Methodsmentioning

confidence: 99%

Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation

et al. 2020

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Protein aggregation and abnormal lipid homeostasis are both implicated in neurodegeneration through unknown mechanisms. Here we demonstrate that aggregate-membrane interaction is critical to induce a form of cell death called ferroptosis. Importantly, the aggregate-membrane interaction that drives ferroptosis depends both on the conformational structure of the aggregate, as well as the oxidation state of the lipid membrane. We generated human stem cell-derived models of synucleinopathy, characterized by the intracellular formation of α-synuclein aggregates that bind to membranes. In human iPSC-derived neurons with SNCA triplication, physiological concentrations of glutamate and dopamine induce abnormal calcium signaling owing to the incorporation of excess α-synuclein oligomers into membranes, leading to altered membrane conductance and abnormal calcium influx. α-synuclein oligomers further induce lipid peroxidation. Targeted inhibition of lipid peroxidation prevents the aggregate-membrane interaction, abolishes aberrant calcium fluxes, and restores physiological calcium signaling. Inhibition of lipid peroxidation, and reduction of iron-dependent accumulation of free radicals, further prevents oligomer-induced toxicity in human neurons. In summary, we report that peroxidation of polyunsaturated fatty acids underlies the incorporation of β-sheet-rich aggregates into the membranes, and that additionally induces neuronal death. This suggests a role for ferroptosis in Parkinson’s disease, and highlights a new mechanism by which lipid peroxidation causes cell death.

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Section: Methodsmentioning

confidence: 99%

Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation

et al. 2020

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“…These fibrillary aggregates are morphologically similar to the amyloid fibrils found in Alzheimer's disease neuritic plaques and in deposits associated with other amyloidogenic diseases [13,14]. In addition to fibrils, advances in the structural elucidation of αS oligomers have been made recently [15,16]. Theories of (i) pore formation followed by membrane leakage [17,18], (ii) receptor-mediated mechanisms [19,20], and (iii) cellular protection by binding with extracellular chaperones [21] have been discussed in terms of the underlying molecular pathology of PD.…”

Section: Introductionmentioning

confidence: 67%

Salient Features of Monomeric Alpha-Synuclein Revealed by NMR Spectroscopy

et al. 2020

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Elucidating the structural details of proteins is highly valuable and important for the proper understanding of protein function. In the case of intrinsically disordered proteins (IDPs), however, obtaining the structural details is quite challenging, as the traditional structural biology tools have only limited use. Nuclear magnetic resonance (NMR) is a unique experimental tool that provides ensemble conformations of IDPs at atomic resolution, and when studying IDPs, a slightly different experimental strategy needs to be employed than the one used for globular proteins. We address this point by reviewing many NMR investigations carried out on the α-synuclein protein, the aggregation of which is strongly correlated with Parkinson’s disease.

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“…Now it is known that aSyn exists in oligomeric form during the lag phase of brillization process. 56,57,[60][61][62][63][64][65][66][67][68][69][70][71][72][73][74] So then a question arises that is the disappearance of peaks for stretches of residues in the free aSyn HSQC spectrum (Fig. 3A) due to the oligomerization of the protein?…”

Section: Resultsmentioning

confidence: 99%