Changes in secondary structure of α-synuclein during oligomerization induced by reactive aldehydes

Cai, Yixiao; Lendel, Christofer; Österlund, Lars; Kasrayan, Alex; Lannfelt, Lars; Ingelsson, Martin; Nikolajeff, Fredrik; Karlsson, Mikael; Bergström, Joakim

doi:10.1016/j.bbrc.2015.06.154

Cited by 20 publications

(28 citation statements)

References 31 publications

(53 reference statements)

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“…For example, deconvolution of CD spectra recently revealed transient α-helical conformers (undetected by NMR) in Aβ 42 ensembles (Misra et al, 2016). A recent technique, combining attenuated total reflectance with FTIR (ATR-FTIR) has revealed secondary structural changes at different stages (including monomers) of reactive aldehyde-induced aggregation in α-syn (Cai et al, 2015). Finally, not all studies require specialized kit; nanoscale liquid chromatography coupled with tandem mass spectrometry (nanoLC-MS) was used to discern in vitro checkpoint kinases, Chk1-and Chk2-mediated sites of Tau phosphorylation (Mendoza, Dolios, & Wang, 2015).…”

Section: Structural and Mechanistic Insights Gleaned From Experiments: Comparison With Simulationsmentioning

confidence: 99%

Revisiting the earliest signatures of amyloidogenesis: Roadmaps emerging from computational modeling and experiment

Bhattacharya

Thompson

2018

WIREs Comput Mol Sci

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Neurodegenerative amyloidogenesis begins with the aggregation of intrinsically disordered proteins (IDPs), which is the first step in a cascade of assembly events that can lead to insoluble fibrous deposits in brain tissue. IDP conformations that promote formation of toxic oligomers remain poorly understood, and are the most fundamental target of putative treatments for neurodegenerative disease. Rapid advances in theory, simulation and experimental methods, hold the promise of reversing protein aggregation by identifying and developing inhibitors of the transient amyloidogenic IDP conformations. To make meaningful progress it is important to appreciate the benefits and limitations of the latest developments in computational methods of conformational and ensemble modeling, and their integration and validation with experiments. Integrated studies are beginning to provide significant conceptual and mechanistic insights, including identification of the properties of amyloidogenic IDPs in their free, unbound form. At the same time, contradicting viewpoints have emerged concerning convergence of IDP ensemble signatures and properties from parallel studies, and there also remains a pressing need to develop physical models that can deliver reliable predictions across different IDP families. Focussing on the four most common amyloidogenic IDPs of Amyloid β, Tau, α‐synuclein and Prions, improvements are proposed for next‐generation models and experiments that can potentially identify drug treatments for neurodegenerative disease via incorporation of the extended cellular environment. This article is categorized under: Molecular and Statistical Mechanics > Molecular Mechanics Structure and Mechanism > Computational Biochemistry and Biophysics Structure and Mechanism > Molecular Structures

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Section: Structural and Mechanistic Insights Gleaned From Experiments: Comparison With Simulationsmentioning

confidence: 99%

Revisiting the earliest signatures of amyloidogenesis: Roadmaps emerging from computational modeling and experiment

Bhattacharya

Thompson

2018

WIREs Comput Mol Sci

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“…ONE (Figure ), on the other hand, stimulated mainly (antiparallel) β‐sheet structure,,, and these ONE‐αSOs were reported to be either spherical or amorphous ,. Their functional relevance is, however, less clear.…”

Section: Large Variety Of α‐Synuclein Oligomeric Speciesmentioning

confidence: 99%

“…These HNE‐αSOs are reported to be either spherical,,, curvilinear,, globular, or ring‐shaped . In addition, both unordered, and (antiparallel) β‐sheet structures,, have been described. HNE‐αSOs are also active in numerous PD‐relevant toxicity assays, underlining their relevance towards PD, where they induced cellular toxicity,, increased uptake in neuronal cells,, increased ROS production, and impaired LTP via N ‐methyl‐ D ‐aspartate (NMDA) receptor activation .…”

Section: Large Variety Of α‐Synuclein Oligomeric Speciesmentioning

confidence: 99%

α‐Synuclein Oligomers: A Study in Diversity

Diggelen

Tepper²,

Apetri³

et al. 2016

Israel Journal of Chemistry

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A critical step in Parkinson's disease (PD) is the formation of toxic α‐synuclein oligomers (αSOs). In vitro αSOs are formed by self‐assembly of α‐synuclein at high concentrations, or by the addition of, for example, dopamine, lipids, ethanol, or metal ions. These αSOs are structurally distinct from the unfolded monomer and aggregated β‐sheet fibrils. Nevertheless, the literature reports a wide variety of αSO shapes, sizes, and proposed toxic mechanisms. This heterogeneous character makes it difficult to form a unifying picture. Here, we present an overview of the different αSO species made in vitro, providing a tool for better comparison of different protocols and the ensuing αSOs, and emphasizing the striking versatility in the appearance and properties of these critical species. We also summarize what is known of the biological activities of different αSOs. Despite a large and increasing level of insight into αSO effects in vitro, we still lack strong insight into the structures and sizes of αSO species formed in vivo. Once this is established, it may be possible to generate more uniform protocols that could stimulate further efforts to develop viable PD biomarker assays and therapies.

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“…Lewy bodies consisting of aggregated α-synuclein are a neuropathological hallmark of PD, and mutations in the α-synuclein gene have been linked to early-onset PD. , Monomeric α-synuclein (αSN, UniProtKB, P37840-1) is an intrinsically disordered protein that has a high propensity to self-associate into oligomers (αSO) and amyloid fibrils. The mechanism of neurodegeneration by α-synuclein is not fully understood, but there is increasing evidence that the oligomeric forms play an important role in cellular toxicity. − Importantly, the oligomerization of monomeric α-synuclein (αSN) is accelerated in vitro by the reactive aldehydes 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE), which are lipid peroxidation products formed under cellular oxidative stress. − There is a substantial increase in lipid peroxidation in the substantia nigra brain region from deceased PD patients, reflecting elevated cellular oxidative stress . HNE and ONE are readily generated under such oxidative conditions in vivo by free-radical-induced peroxidation of the polyunsaturated fatty acids (PUFAs) arachidonic acid and docosahexaenoic acid. − Both HNE and ONE can chemically modify and cross-link proteins via Cys, His, and Lys residues and thereby impair protein function .…”

Section: Introductionmentioning

confidence: 99%

Lipid Peroxidation Products HNE and ONE Promote and Stabilize Alpha-Synuclein Oligomers by Chemical Modifications

et al. 2021

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The aggregation of α-synuclein (αSN) and increased oxidative stress leading to lipid peroxidation are pathological characteristics of Parkinson's disease (PD). Here, we report that aggregation of αSN in the presence of lipid peroxidation products 4-hydroxy-2-nonenal (HNE) and 4-oxo-2nonenal (ONE) increases the stability and the yield of αSN oligomers (αSO). Further, we show that ONE is more efficient than HNE at inducing αSO. In addition, we demonstrate that the two αSO differ in both size and shape. ONE-αSO are smaller in size than HNE-αSO, except when they are formed at a high molar excess of aldehyde. In both monomeric and oligomeric αSN, His50 is the main target of HNE modification, and HNE-induced oligomerization is severely retarded in the mutant His50Ala αSN. In contrast, ONE-induced aggregation of His50Ala αSN occurs readily, demonstrating the different pathways for inducing αSN aggregation by HNE and ONE. Our results show different morphologies of the HNE-treated and ONE-treated αSO and different roles of His50 in their modification of αSN, but we also observe structural similarities between these αSO and the non-treated αSO, e.g., flexible C-terminus, a folded core composed of the N-terminal and NAC region. Furthermore, HNE-αSO show a similar deuterium uptake as a previously characterized oligomer formed by non-treated αSO, suggesting that the backbone conformational dynamics of their folded cores resemble one another.

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Changes in secondary structure of α-synuclein during oligomerization induced by reactive aldehydes

Cited by 20 publications

References 31 publications

Revisiting the earliest signatures of amyloidogenesis: Roadmaps emerging from computational modeling and experiment

Revisiting the earliest signatures of amyloidogenesis: Roadmaps emerging from computational modeling and experiment

α‐Synuclein Oligomers: A Study in Diversity

Lipid Peroxidation Products HNE and ONE Promote and Stabilize Alpha-Synuclein Oligomers by Chemical Modifications

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