Structural Properties of Pore-Forming Oligomers of α-Synuclein

Kim, Hai Young; Cho, Min Kyu; Kumar, Ashutosh; Maier, Elke; Siebenhaar, Carsten; Becker, Stefan; Fernandez, Claudio O.; Lashuel, Hilal A.; Benz, Roland; Lange, Adam; Zweckstetter, Markus

doi:10.1021/ja9077599

Cited by 186 publications

(173 citation statements)

References 38 publications

(72 reference statements)

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“…It has been proposed, that α-Syn oligomers may penetrate the cell membrane generating voltage-gated channels. 24 Alternatively, the loss of α-Syn function due to aggregation may cause PD. 5,56 Finally, a recent study showed that in vitro the aggregation of α-Syn into amyloid fibrils is driven by physiologically irrelevant air-water interfaces 57 thus questioning the validity of the current knowledge on α-Syn nucleation and aggregation.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Membrane Interaction and Disruption by α-Synuclein

et al. 2011

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Parkinson's disease is a common progressive neurodegenerative condition, characterized by the deposition of amyloid fibrils as Lewy bodies in the substantia nigra of affected individuals. These insoluble aggregates predominantly consist of the protein -synuclein. There is increasing evidence suggesting that the aggregation of -synuclein is influenced by lipid membranes and, vice versa, the membrane integrity is severely affected by the presence of bound aggregates. Here, using the surface-sensitive imaging technique supercritical angle fluorescence microscopy and Förster resonance energy transfer, we report the direct observation of -synuclein aggregation on supported lipid bilayers. Both the wild-type and the two mutant forms of -synuclein studied, namely, the familiar variant A53T and the designed highly toxic variant E57K, were found to follow the same mechanism of polymerization and membrane damage. This mechanism involved the extraction of lipids from the bilayer and their clustering around growing -synuclein aggregates. Despite all three isoforms following the same pathway, the extent of aggregation and their effect on the bilayers was seen to be variant and concentration dependent. Both A53T and E57K formed cross--sheet aggregates and damaged the membrane at submicromolar concentrations. The wild-type also formed aggregates in this range; however, the extent of membrane disruption was greatly reduced. The process of membrane damage could resemble part of the yet poorly understood cellular toxicity phenomenon in vivo. AbstractParkinson`s disease is a common progressive neurodegenerative condition, characterized by the deposition of amyloid fibrils as Lewy bodies in the substantia nigra of affected individuals. These insoluble aggregates predominantly consist of the protein α-Synuclein. There is increasing evidence suggesting that the aggregation of α−Synuclein is influenced by lipid membranes and, vice versa, the membrane integrity is severely affected by the presence of bound aggregates. Here, using the surface sensitive imaging technique super critical angle fluorescence microscopy and Förster resonance energy transfer we report the direct observation of α−Synuclein aggregation on supported lipid bilayers. Both the wild-type and the two mutant forms of α−Synuclein studied, namely the familiar variant A53T and the designed highly toxic variant E57K, were found to follow the same mechanism of polymerization and membrane damage. This mechanism involved the extraction of lipids from the bilayer and their clustering around growing α−Synuclein aggregates. Despite all three isoforms following the same pathway, the extent of aggregation and their effect on the bilayers was seen to be variant and concentration dependent. Both A53T and E57K formed cross β-sheet aggregates and damaged the membrane at sub-micromolar concentrations. The wild-type also formed aggregates in this range; however, the extent of membrane disruption was greatly reduced. The process of membrane damage could resemble the yet poorly...

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Section: Discussionmentioning

confidence: 99%

Mechanism of Membrane Interaction and Disruption by α-Synuclein

et al. 2011

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“…The oligomers were harvested at 16 h, which corresponds to the lag phase. The fact that these species do not enhance ThT fluorescence suggests that they may lack the cross-␤-structure characteristic of amyloid fibrils (54). In fact, the ␣-SN oligomers appeared as spheroidal and polydisperse species as shown by transmission electron microscopy (Fig.…”

Section: Hi-gapdh Ess Modifies ␣-Sn Oli Toxicity and Membranementioning

confidence: 93%

Structural Characterization of Heparin-induced Glyceraldehyde-3-phosphate Dehydrogenase Protofibrils Preventing α-Synuclein Oligomeric Species Toxicity

Ávila

Torres-Bugeau

Barbosa

et al. 2014

Journal of Biological Chemistry

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Background: Although glycosaminoglycan-induced GAPDH prefibrillar species accelerates ␣-synuclein aggregation, its role in toxicity remains unclear. Results: The toxic effect exerted by ␣-synuclein oligomers on cell culture was abolished by GAPDH protofibril, which was identified and structurally characterized. Conclusion: GAPDH protofibrils can efficiently sequester ␣-synuclein toxic oligomers. Significance: GAPDH protofibrils may play an important role in neuronal proteostasis and could open a novel therapeutic strategy for synucleinopathies.

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“…In preliminary experiments, we attempted to investigate the interaction of anle138b with a specific type of in-vitro generated α-synuclein oligomers [42,43], and did not observe a change in fluorescence representative for rigid binding. This could be due to e.g., a missing interaction of anle138b to this specific type of oligomer [43,44] or due to no significant change of the fluorescence properties of anle138b upon binding, or a rapid disintegration of the oligomeric structure upon binding the DPP-compound. Studies with more elaborate techniques are required to treat this important subject.…”

Section: Tablementioning

confidence: 99%

Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to α-synuclein aggregates

Deeg

Reiner

Schmidt

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background: Special diphenyl-pyrazole compounds and in particular anle138b were found to reduce the progression of prion and Parkinson's disease in animal models. The therapeutic impact of these compounds was attributed to the modulation of α-synuclein and prion-protein aggregation related to these diseases. Methods: Photophysical and photochemical properties of the diphenyl-pyrazole compounds anle138b, anle186b and sery313b and their interaction with monomeric and aggregated α-synuclein were studied by fluorescence techniques. Results: The fluorescence emission of diphenyl-pyrazole is strongly increased upon incubation with α-synuclein fibrils, while no change in fluorescence emission is found when brought in contact with monomeric α-synuclein. This points to a distinct interaction between diphenyl-pyrazole and the fibrillar structure with a high binding affinity (K d = 190 ± 120 nM) for anle138b. Several α-synuclein proteins form a hydrophobic binding pocket for the diphenyl-pyrazole compound. A UV-induced dehalogenation reaction was observed for anle138b which is modulated by the hydrophobic environment of the fibrils. Conclusion: Fluorescence of the investigated diphenyl-pyrazole compounds strongly increases upon binding to fibrillar α-synuclein structures. Binding at high affinity occurs to hydrophobic pockets in the fibrils. General significance: The observed particular fluorescence properties of the diphenyl-pyrazole molecules open new possibilities for the investigation of the mode of action of these compounds in neurodegenerative diseases. The high binding affinity to aggregates and the strong increase in fluorescence upon binding make the compounds promising fluorescence markers for the analysis of aggregation-dependent epitopes.

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Structural Properties of Pore-Forming Oligomers of α-Synuclein

Cited by 186 publications

References 38 publications

Mechanism of Membrane Interaction and Disruption by α-Synuclein

Mechanism of Membrane Interaction and Disruption by α-Synuclein

Structural Characterization of Heparin-induced Glyceraldehyde-3-phosphate Dehydrogenase Protofibrils Preventing α-Synuclein Oligomeric Species Toxicity

Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to α-synuclein aggregates

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