α-Synuclein in α-helical conformation at air–water interface: implication of conformation and orientation changes during its accumulation/aggregation

Wang, Chengshan; Shah, Nilam C.; Thakur, Garima; Zhou, Feimeng; Leblanc, Roger M.

doi:10.1039/c0cc02098b

Cited by 34 publications

(47 citation statements)

References 22 publications

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“…Previous work has shown that the process of nucleation of α-synuclein amyloid fibrils is likely to be heterogeneous and catalyzed by environmental features, such as air-water interfaces (26,27), lipid bilayers (28), SDS micelles and other anionic surfactants (11,29,30), or artificial interfaces such as the coatings of containers or stir bars (31). In addition, mechanical action, such as shaking and stirring, is often used to accelerate the aggregation of α-synuclein (32).…”

Section: Primary Nucleation and Fragmentation Can Be Selectively Enhamentioning

confidence: 99%

Solution conditions determine the relative importance of nucleation and growth processes in α-synuclein aggregation

Buell

Galvagnion

Gaspar³

et al. 2014

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

587

867

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The formation of amyloid fibrils by the intrinsically disordered protein α-synuclein is a hallmark of Parkinson disease. To characterize the microscopic steps in the mechanism of aggregation of this protein we have used in vitro aggregation assays in the presence of preformed seed fibrils to determine the molecular rate constant of fibril elongation under a range of different conditions. We show that α-synuclein amyloid fibrils grow by monomer and not oligomer addition and are subject to higher-order assembly processes that decrease their capacity to grow. We also find that at neutral pH under quiescent conditions homogeneous primary nucleation and secondary processes, such as fragmentation and surface-assisted nucleation, which can lead to proliferation of the total number of aggregates, are undetectable. At pH values below 6, however, the rate of secondary nucleation increases dramatically, leading to a completely different balance between the nucleation and growth of aggregates. Thus, at mildly acidic pH values, such as those, for example, that are present in some intracellular locations, including endosomes and lysosomes, multiplication of aggregates is much faster than at normal physiological pH values, largely as a consequence of much more rapid secondary nucleation. These findings provide new insights into possible mechanisms of α-synuclein aggregation and aggregate spreading in the context of Parkinson disease.seeding | prion-like behavior | neurodegenerative disease | kinetic analysis | electrostatic interactions T he conversion of soluble peptide and protein molecules into insoluble amyloid fibrils is of great interest in fields of science ranging from molecular medicine to nanotechnology (1). The formation of amyloid fibrils is a characteristic feature of a substantial number of increasingly common medical disorders, including neurodegenerative conditions such as Alzheimer's and Parkinson diseases (2). Elucidating the fundamental mechanistic steps involved in the conversion from the soluble to the fibrillar forms of the peptides and proteins involved in such disorders is crucial for understanding their origin and proliferation, and hence for exploring in a rational manner new and effective therapeutic strategies through which to combat their onset or progression (3).One general aspect of amyloid diseases is that once the first aggregates are formed it is very difficult to stop or reverse the aggregation process. This implies that aggregation needs to be studied in both the absence and presence of preformed aggregates, commonly known as seeds, to deepen our understanding of the mechanism of the self-assembly process in vivo. It is possible to define from in vitro studies the rate constants for the multiplicity of microscopic steps that increase the number and total mass of the different types of aggregates that are populated during this process. Such an analysis has recently been carried out for the Aβ42 peptide (4) associated with Alzheimer's disease by combining experimental and theoretical methodolo...

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Section: Primary Nucleation and Fragmentation Can Be Selectively Enhamentioning

confidence: 99%

Solution conditions determine the relative importance of nucleation and growth processes in α-synuclein aggregation

Buell

Galvagnion

Gaspar³

et al. 2014

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

587

867

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“…Studying Cu(II) binding by α-helical α-syn should be more biologically relevant, because α-syn is highly populated at the presynaptic termini (PST) and remains at such an interface in the α-helical conformation [19,20]. Moreover, release of metal ions by neurons during their depolarization and neurotransmission is also an interfacial process.…”

Section: Introductionmentioning

confidence: 99%

Conversion of natively unstructured α-synuclein to its α-helical conformation significantly attenuates production of reactive oxygen species

Zhou¹,

Hao²,

Wang³

et al. 2013

Journal of Inorganic Biochemistry

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The intracellular α-synuclein (α-syn) protein, whose conformational change and aggregation have been closely linked to the pathology of Parkingson’s disease (PD), is highly populated at the presynaptic termini and remains there in the α-helical conformation. In this study, circular dichroism confirmed that natively unstructured α-syn in aqueous solution was transformed to its α-helical conformation upon addition of trifluoroethanol (TFE). Electrochemical and UV–visible spectroscopic experiments reveal that both Cu(I) and Cu(II) are stabilized, with the former being stabilized by about two orders of magnitude. Compared to unstructured α-syn (Binolfi et al., J. Am. Chem. Soc. 133 (2011) 194–196), α-helical α-syn stabilizes Cu(I) by more than three orders of magnitude. Through the measurements of H2O2 and hydroxyl radicals (OH•) in solutions containing different forms of Cu(II) (free and complexed by unstructured or α-helical α-syn), we demonstrate that the significantly enhanced Cu(I) binding affinity helps inhibit the production of highly toxic reactive oxygen species, especially the hydroxyl radicals. Our study provides strong evidence that, as a possible means to prevent neuronal cell damage, conversion of the natively unstructured α-syn to its α-helical conformation in vivo could significantly attenuate the copper-modulated ROS production.

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“…Typical secondary structures (also called conformations) are α−helix, β−sheets, and random coil [12][13][14]. Random coil structure is also called unstructured conformation, in which the polypeptide chain is well dissolved in the aqueous solution and moves freely in the aqueous environment.…”

Section: Background Of Peptides/proteinsmentioning

confidence: 99%

“…The technique of IRRAS for the Langmuir monolayer was developed in 1985 [33]. Subsequently, some proteins were shown to be also able to form a Lanmguir monolayer and IRRAS has been consequently used to analyze protein samples in the Langmuir monolayer [14,[34][35][36][37][38], which covers the surface of H 2 O. IRRAS can not only detect the FTIR signal of proteins, but also valuate the orientation of the proteins sample in the Langmuir monolayer due to the selection rules as discussed below [14,[34][35][36]38].…”

Section: Irras Studies Of Proteins At the Air-water Interfacementioning

confidence: 99%

Surface FTIR Techniques to Analyze the Conformation of Proteins/ Peptides in H2O Environment

Combs¹,

Gonzalez²,

Wang³

2016

J Phys Chem Biophys

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α-Synuclein in α-helical conformation at air–water interface: implication of conformation and orientation changes during its accumulation/aggregation

Cited by 34 publications

References 22 publications

Solution conditions determine the relative importance of nucleation and growth processes in α-synuclein aggregation

Solution conditions determine the relative importance of nucleation and growth processes in α-synuclein aggregation

Conversion of natively unstructured α-synuclein to its α-helical conformation significantly attenuates production of reactive oxygen species

Surface FTIR Techniques to Analyze the Conformation of Proteins/ Peptides in H2O Environment

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