Different Types Of Oligomers Research Articles

The Role of α-Synuclein Oligomers in Parkinson's Disease.

α-synuclein (α-syn) is a protein associated with the pathogenesis of Parkinson’s disease (PD), the second most common neurodegeneration disease with no effective treatment. However, how α-syn drives the pathology of PD remains elusive. Recent studies suggest that α-syn oligomers are the primary cause of neurotoxicity and play a critical role in PD. In this review, we discuss the process of α-syn oligomers formation and the current understanding of the structures of oligomers. We also describe seed and propagation effects of oligomeric forms of α-syn. Then, we summarize the mechanism by which α-syn oligomers exert neurotoxicity and promote neurodegeneration, including mitochondrial dysfunction, endoplasmic reticulum stress, proteostasis dysregulation, synaptic impairment, cell apoptosis and neuroinflammation. Finally, we investigate treatment regimens targeting α-syn oligomers at present. Further research is needed to understand the structure and toxicity mechanism of different types of oligomers, so as to provide theoretical basis for the treatment of PD.

Quantum chemical study on gas-phase oligomerization in AlGaN MOCVD growth

The gas-phase oligomerization reaction path in the growth of AlGaN by MOCVD has been calculated using quantum chemical calculations with density functional theory. The oligomerization of two types amides DMAlNH2 and DMGaNH2 (including heterogeneous oligomerization and homogeneous oligomerization) and subsequent CH4 elimination reactions were investigated at different temperatures. The degree for formation of the various oligomers and the different types of oligomers that could appear at different temperature ranges has been analyzed. DMAlNH2 has a stronger oligomerization ability than DMGaNH2, and the presence of DMAlNH2 can promote DMGaNH2 to form heterogeneous oligomers, which successfully explains the gas phase scavenging effect. Dimers are mainly oligomers in gas phase and their CH4 elimination reactions are mainly intramolecular reactions rather than intermolecular reactions. Pure gas [AlN] or [GaN] molecules are theoretically impossible to form.

Challenges in understanding the structure/activity relationship of Aβ oligomers

A major hallmark of Alzheimer’s disease (AD) is the accumulation and deposition of fibrillar aggregates of the amyloid-b (Ab) peptide into neuritic plaques. These amyloid deposits were thought to play a central role in AD; however, the correlation between plaque load and disease is weak. Increasing evidence supports the notion that a variety of small, globular aggregates of Ab, referred to broadly as Ab oligomers (AbO), may in fact be the primary culprits associated with neurotoxicity. Evaluation of AbO structure and physiological activity is complicated by their metastability, heterogeneity, complex aggregation pathways, and dependence on experimental conditions. Numerous different types of oligomers have been reported, and these have been associated with varying degrees of toxicity and modes of interaction. Here, we briefly review AbOs with a focus on their formation, structure, and biophysical methods applied to their investigation.

Copper Binding Induces Polymorphism in Amyloid-β Peptide: Results of Computational Models.

Amyloid-β (Aβ) peptides are intrinsically disordered peptides, and their aggregation is the hallmark of Alzheimer's disease development. The propensity of the Aβ peptide to intermolecular interactions, the latter favoring different types of oligomers and aggregated forms, has been the object of a huge number of studies. Several facts are now established: the presence of large amount of d-block (M) ions (Zn, Cu, and Fe) in the aggregated forms; the 1:1 M/Aβ ratio favors the formation of amorphous aggregates, with an aggregation rate lower than that in the absence of such ions. In particular, statistical models describing the interactions between copper and amyloid peptides are mandatory to explain the relationship between neurodegeneration, copper dyshomeostasis, and overproduction of reactive oxygen species, the latter event occurring with aging. In this work, we show, by replica-exchange molecular dynamics simulations, that a copper ion (Cu2+) bound as in the experimentally observed prevailing coordination enhances the probability of closed structures that hinder the formation of extended intermolecular hydrogen bonds that stabilize fibrillar ordered aggregated forms. On the other hand, this effect enhances the catalytic role of the complex during the lifetime of soluble forms.

Backbone NMR assignments of HypF-N under conditions generating toxic and non-toxic oligomers

The HypF protein is involved in the maturation and regulation of hydrogenases. The N-terminal domain of HypF (HypF-N) has served as a key model system to study the pathways of protein amyloid formation and the nature of the toxicity of pre-fibrilar protein oligomers. This domain can aggregate into two forms of oligomers having significantly different toxic effects when added to neuronal cultures. Here, NMR assignments of HypF-N backbone resonances are presented in its native state and under the conditions favouring the formation of toxic and non-toxic oligomers. The analyses of chemical shifts provide insights into the protein conformational state and the possible pathways leading to the formation of different types of oligomers.

Binding affinity of amyloid oligomers to cellular membranes is a generic indicator of cellular dysfunction in protein misfolding diseases.

The conversion of peptides or proteins from their soluble native states into intractable amyloid deposits is associated with a wide range of human disorders. Misfolded protein oligomers formed during the process of aggregation have been identified as the primary pathogenic agents in many such conditions. Here, we show the existence of a quantitative relationship between the degree of binding to neuronal cells of different types of oligomers formed from a model protein, HypF-N, and the GM1 content of the plasma membranes. In addition, remarkably similar behavior is observed for oligomers of the Aβ42 peptide associated with Alzheimer’s disease. Further analysis has revealed the existence of a linear correlation between the level of the influx of Ca2+ across neuronal membranes that triggers cellular damage, and the fraction of oligomeric species bound to the membrane. Our findings indicate that the susceptibility of neuronal cells to different types of misfolded oligomeric assemblies is directly related to the extent of binding of such oligomers to the cellular membrane.

Effect of sealing with ultraviolet‐curable adhesives on the performance of dye‐sensitized solar cells

ABSTRACTIn this study, we investigated different types of oligomers, including an aliphatic polyester‐based urethane diacrylate (CN 991) and aliphatic hydrophobic backbone (CN 9014), and different contents of the oligomers and different amounts of 2‐(perfluorohexyl) ethyl methacrylate (PFE) monomer in ultraviolet (UV)‐curable adhesive to explore the effects of their resistance to corrosion on the basis of the electrolyte, adhesion strength, and performance of the sealing of dye‐sensitized solar cells (DSSCs). The DSSCs were sealed with a 58% CN 9014 containing UV‐curable adhesive mixed with 3.0 wt % PFE monomer, which had the greatest open‐circuit voltage and short‐circuit current density. A 4.8% efficiency was obtained after the sample underwent long‐term thermal stability tests at 60°C for 37 days. The performance of the 3.0 wt % PFE‐containing UV‐curable adhesive in the sealing of DSSCs was better than that of Surlyn for long‐term thermal stability. In addition, this adhesive provided better resistance to corrosion because of the electrolyte and enhanced the DSSCs' durability. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 42015.

Correction to “Formation of Two Different Types of Oligomers in the Early Phase of pH-Induced Aggregation of the Alzheimer Aβ(12-28) Peptide”

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionORIGINAL ARTICLEThis notice is a correctionCorrection to “Formation of Two Different Types of Oligomers in the Early Phase of pH-Induced Aggregation of the Alzheimer Aβ(12-28) Peptide”Paulami Mandal, Nadejda Eremina, and Andreas Barth*Cite this: J. Phys. Chem. B 2014, 118, 11, 3243–3244Publication Date (Web):March 10, 2014Publication History Published online10 March 2014Published inissue 20 March 2014https://doi.org/10.1021/jp5010242Copyright © 2014 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views195Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (120 KB) Get e-Alerts Get e-Alerts

The Molecular Basis of Iron-induced Oligomerization of Frataxin and the Role of the Ferroxidation Reaction in Oligomerization

The role of the mitochondrial protein frataxin in iron storage and detoxification, iron delivery to iron-sulfur cluster biosynthesis, heme biosynthesis, and aconitase repair has been extensively studied during the last decade. However, still no general consensus exists on the details of the mechanism of frataxin function and oligomerization. Here, using small-angle x-ray scattering and x-ray crystallography, we describe the solution structure of the oligomers formed during the iron-dependent assembly of yeast (Yfh1) and Escherichia coli (CyaY) frataxin. At an iron-to-protein ratio of 2, the initially monomeric Yfh1 is converted to a trimeric form in solution. The trimer in turn serves as the assembly unit for higher order oligomers induced at higher iron-to-protein ratios. The x-ray crystallographic structure obtained from iron-soaked crystals demonstrates that iron binds at the trimer-trimer interaction sites, presumably contributing to oligomer stabilization. For the ferroxidation-deficient D79A/D82A variant of Yfh1, iron-dependent oligomerization may still take place, although >50% of the protein is found in the monomeric state at the highest iron-to-protein ratio used. This demonstrates that the ferroxidation reaction controls frataxin assembly and presumably the iron chaperone function of frataxin and its interactions with target proteins. For E. coli CyaY, the assembly unit of higher order oligomers is a tetramer, which could be an effect of the much shorter N-terminal region of this protein. The results show that understanding of the mechanistic features of frataxin function requires detailed knowledge of the interplay between the ferroxidation reaction, iron-induced oligomerization, and the structure of oligomers formed during assembly.

Single Molecule AFM Force Spectroscopy Analysis of Alpha-Synuclein Misfolding

Protein misfolding is a transient state during self-assembly into aggregates defining the molecular mechanism of the development of Alzheimer's, Parkinson's and other neurodegenerative diseases. Misfolding and aggregation of alpha-synuclein (α-Syn) is tightly linked to the development of Parkinson's disease. Here we applied single molecule AFM force spectroscopy (SMFS) to probe transient misfolded states of α-Syn measuring pair-wise interactions between individual α-Syn molecules at conditions that induce conformational transitions associated with enhanced aggregation. In the SMFS approach we probed the interactions between α-Syn covalently attached to the AFM probe and substrate by the C-terminal cysteine. We show that at conditions close to physiological, addition of spermidine results in dramatic increase of the protein's propensity to misfold. Additionally, using SMFS we detected and characterized misfolded dimers of α-Syn, the simplest aggregated form of α-Syn. Our results demonstrate that more than one segment within the protein molecule is responsible for the initial association of α-Syn into dimers and potentially into higher-order oligomers and fibrils. This finding suggests that even the first step of α-Syn self-assembly (dimerization) possesses a certain degree of heterogeneity. We hypothesize that these different misfolded conformations can lead to different types of oligomers and define the aggregation pathway. The marked differences in the misfolding patterns between WT α-Syn and single point mutants might be responsible for the higher propensity of the mutants to aggregate and cause early-onset PD.The work was supported by grants to YLL from National Institutes of Health (1P01GM091743-01A1 and 1 R01 GM096039-01A1), U.S. Department of Energy Grant DE-FG02-08ER64579, National Science Foundation (EPS - 1004094) and the Nebraska Research Initiative.

Formation of Two Different Types of Oligomers in the Early Phase of pH-Induced Aggregation of the Alzheimer Aβ(12-28) Peptide

The early phase in the aggregation process of the Alzheimer's peptide Aβ(12-28) with both protected and unprotected ends was studied by time-resolved infrared spectroscopy and circular dichroism spectroscopy. Aggregation in the time-resolved experiments was initiated by a rapid pH drop caused by the photolysis of 1-(2-nitrophenyl)ethyl sulfate (caged sulfate). The infrared spectra indicate aggregates from both versions of the Aβ(12-28) peptide. [corrected] They form fast (within 60 ms), presumably from initial aggregates, and their spectral signature is consistent with a β-barrel structure. The other type arises relatively slowly from unstructured monomers on the seconds-to-minutes time scale and forms at lower pH than the first type. These β sheets are antiparallel, planar, and large and show an absorption band at 1622 cm(-1) that shifts to 1617 cm(-1) in 12 min with most of the shift occurring in 10 s.

Continuous Flow Reactor for the Production of Stable Amyloid Protein Oligomers

The predominant working hypothesis of Alzheimer's disease is that the proximate pathologic agents are oligomers of the amyloid β-protein (Aβ). "Oligomer" is an ill-defined term. Many different types of oligomers have been reported, and they often exist in rapid equilibrium with monomers and higher-order assemblies. This has made formal structure-activity determinations difficult. Recently, Ono et al. [Ono, K., et al. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 14745-14750] used rapid, zero-length, in situ chemical cross-linking to stabilize the oligomer state, allowing the isolation and study of pure populations of oligomers of a specific order (number of Aβ monomers per assembly). This approach was successful but highly laborious and time-consuming, precluding general application of the method. To overcome these difficulties, we developed a "continuous flow reactor" with the ability to produce theoretically unlimited quantities of chemically stabilized Aβ oligomers. We show, in addition to its utility for Aβ, that this method can be applied to a wide range of other amyloid-forming proteins.

Single-Molecule Atomic Force Microscopy Force Spectroscopy Study of Aβ-40 Interactions

Misfolding and aggregation of amyloid β-40 (Aβ-40) peptide play key roles in the development of Alzheimer's disease (AD). However, very little is known about the molecular mechanisms underlying these molecular processes. We developed a novel experimental approach that can directly probe aggregation-prone states of proteins and their interactions. In this approach, the proteins are anchored to the surface of the atomic force microscopy substrate (mica) and the probe, and the interaction between anchored molecules is measured in the approach-retraction cycles. We used dynamic force spectroscopy (DFS) to measure the stability of transiently formed dimers. One of the major findings from DFS analysis of α-synuclein (α-Syn) is that dimeric complexes formed by misfolded α-Syn protein are very stable and dissociate over a range of seconds. This differs markedly from the dynamics of monomers, which occurs on a microsecond to nanosecond time scale. Here we applied the same approach to quantitatively characterize interactions of Aβ-40 peptides over a broad range of pH values. These studies showed that misfolded dimers are characterized by lifetimes in the range of seconds. This value depends on pH and varies between 2.7 s for pH 2.7 and 0.1 s for pH 7, indicating that the aggregation properties of Aβ-40 are modulated by the environmental conditions. The analysis of the contour lengths revealed the existence of various pathways for dimer dissociation, suggesting that dimers with different conformations are formed. These structural variations result in different aggregation pathways, leading to different types of oligomers and higher-order aggregates, including fibrils.

Diffusion of hydrophobin proteins in solution and interactions with a graphite surface

BackgroundHydrophobins are small proteins produced by filamentous fungi that have a variety of biological functions including coating of spores and surface adhesion. To accomplish these functions, they rely on unique interface-binding properties. Using atomic-detail implicit solvent rigid-body Brownian dynamics simulations, we studied the diffusion of HFBI, a class II hydrophobin from Trichoderma reesei, in aqueous solution in the presence and absence of a graphite surface.ResultsIn the simulations, HFBI exists in solution as a mixture of monomers in equilibrium with different types of oligomers. The oligomerization state depends on the conformation of HFBI. When a Highly Ordered Pyrolytic Graphite (HOPG) layer is present in the simulated system, HFBI tends to interact with the HOPG layer through a hydrophobic patch on the protein.ConclusionsFrom the simulations of HFBI solutions, we identify a tetrameric encounter complex stabilized by non-polar interactions between the aliphatic residues in the hydrophobic patch on HFBI. After the formation of the encounter complex, a local structural rearrangement at the protein interfaces is required to obtain the tetrameric arrangement seen in HFBI crystals. Simulations performed with the graphite surface show that, due to a combination of a geometric hindrance and the interaction of the aliphatic sidechains with the graphite layer, HFBI proteins tend to accumulate close to the hydrophobic surface.

Cloud condensation nuclei (CCN) activity and oxygen-to-carbon elemental ratios following thermodenuder treatment of organic particles grown by α-pinene ozonolysis

The effects of thermodenuder treatment on the cloud condensation nuclei (CCN) activity and elemental composition of organic particles grown by α-pinene ozonolysis were investigated. The secondary organic material (SOM) was produced in a continuous-flow chamber, with steady-state organic particle mass concentrations M(org) ranging from 1.4 to 37 μg m(-3). Particles exiting in the outflow were heated to temperatures T of up to 100 °C in a thermodenuder. The oxygen-to-carbon (O:C) and hydrogen-to-carbon (H:C) ratios were measured by on-line mass spectrometry. The observed elemental ratios were fit by a linear function, given by (H:C) = -0.8 (O:C) +1.8 for 0.38 < O:C < 0.50. This fit included the dependence on both M(org) and T, meaning that the single variable of post-thermodenuder M(org) was sufficient as an accurate predictor for O:C(M(org)(T)) and H:C(M(org)(T)). This result suggests that equilibrium partitioning theory largely governed the initial volatilization in the thermodenuder. By comparison, the CCN activity had a different dependence on thermodenuder treatment. At 25 °C, the CCN activity was independent of M(org), having an effective hygroscopicity parameter κ(org) of 0.103 ± 0.002. At 100 °C, however, κ(org) varied from 0.105 for M(org) = 1.4 μg m(-3) to 0.079 for M(org) = 37 μg m(-3), indicating that for high mass concentration the CCN activity decreased with heat treatment. The interpretation is that the oligomer fraction of the SOM increased at elevated T, both because of particle-phase reactions that produced oligomers under those conditions and because of the relative enrichment of lower-volatility oligomers in the SOM accompanying the evaporation of higher-volatility monomers from the SOM. Oligomers have high effective molecular weights and thereby significantly influence CCN activity. The production rates of different types of oligomers depend on the types and concentrations of functional groups present in the SOM, which in turn are strongly influenced by M(org). We conclude with a hypothesis, which is supported by a detailed molecular kinetic model, that the changes in κ(org) at high T were more significant at high compared to low M(org) because particle-phase SOM at high M(org) contained a mix of functional groups favorable to oligomerization, such as carbonyl groups.

Complement Protein C1q Forms a Complex with Cytotoxic Prion Protein Oligomers

A growing number of studies have investigated the interaction between C1q and PrP, but the oligomeric form of PrP involved in this interaction remains to be determined. Aggregation of recombinant full-length murine PrP in the presence of 100 mm NaCl allowed us to isolate three different types of oligomers by size-exclusion chromatography. In contrast to PrP monomers and fibrils, these oligomers activate the classical complement pathway, the smallest species containing 8-15 PrP protomers being the most efficient. We used Thioflavine T fluorescence to monitor PrP aggregation and showed that, when added to the reaction, C1q has a cooperative effect on PrP aggregation and leads to the formation of C1q-PrP complexes. In these complexes, C1q interacts through its globular domains preferentially with the smallest oligomers, as shown by electron microscopy, and retains the ability to activate the classical complement pathway. Using two cell lines, we also provide evidence that C1q inhibits the cytotoxicity induced by the smallest PrP oligomers. The cooperative interaction between C1q and PrP could represent an early step in the disease, where it prevents elimination of the prion seed, leading to further aggregation.

The Role of Small Oligomers on an Amyloidogenic Free Energy Landscape

We combine atomic force microscopy particle size distribution measurements with earlier measurements on 1-anilino-8-naphthalene sulfonate, thioflavin T and dynamic light scattering to develop a quantitative kinetic model for the aggregation of beta-lactoglobulin into amyloid. We directly compare our simulations to the population distributions provided by dynamic light scattering and atomic force microscopy. We combine species in the simulation according to structural type to compare with the fluorescence fingerprint results. The kinetic model of amyloidogenesis leads to an aggregation free energy landscape. We define the roles of and propose a classification scheme for different oligomeric species based on their location on the aggregation free energy landscape. We relate the different types of oligomers to the amyloid cascade hypothesis and the toxic oligomer hypothesis for amyloid-related diseases. We discuss existing kinetic mechanisms in terms of the different types of oligomers. We provide a possible resolution to the toxic oligomer-amyloid coincidence.

Amyloid Oligomer Structures and Toxicity

Amyloid accumulation is commonly associated with a number of important human degenerative diseases and recent findings indicate that soluble amyloid oligomers may represent the primary pathological species in degenerative diseases. Amyloid oligomers are structurally and morphologically diverse, raising the question on whether this diversity is pathologically significant and whether different types of oligomers may have different toxic activities. Many of the amyloids associated with neurodegenerative diseases form three immunologically distinct types of oligomers. Fibrillar oligomers are structurally related to fibrils and may represent small pieces of fibrils or fibril protofilaments. Prefibrillar oligomers are kinetic intermediates in fibril formation and annular protofibrils that resemble membrane pores. These three classes of oligomers share common structures and toxic activities. Focus on these common mechanisms of toxicity provides a means of simplifying the list of primary disease mechanisms and opens the possibility of developing broad spectrum therapeutics that target several amyloid related degenerative diseases.

Role of Small Oligomers on the Amyloidogenic Aggregation Free-Energy Landscape

We combine atomic-force-microscopy particle-size-distribution measurements with earlier measurements on 1-anilino-8-naphthalene sulfonate, thioflavin T, and dynamic light scattering to develop a quantitative kinetic model for the aggregation of β-lactoglobulin into amyloid. We directly compare our simulations to the population distributions provided by dynamic light scattering and atomic force microscopy. We combine species in the simulation according to structural type for comparison with fluorescence fingerprint results. The kinetic model of amyloidogenesis leads to an aggregation free-energy landscape. We define the roles of and propose a classification scheme for different oligomeric species based on their location in the aggregation free-energy landscape. We relate the different types of oligomers to the amyloid cascade hypothesis and the toxic oligomer hypothesis for amyloid-related diseases. We discuss existing kinetic mechanisms in terms of the different types of oligomers. We provide a possible resolution to the toxic oligomer–amyloid coincidence.

Effects of vitrification on the isothermal polymerization of acrylate blends under radiation

The radiation-induced polymerization of some acrylate oligomers was investigated by means of FT-IR spectroscopy applied to films of various thickness that were cured under isothermal conditions. Different types of oligomers, one polyethyleneglycol diacrylate (PEGDA), one polyurethane triacrylate (PURTA), and one epoxy diacrylate derived from bis-phenol A (EPDA) were selected for their contrasting networks properties, with a low, intermediate, and high T g of the radiation-cured materials, respectively. In order to gain a deeper insight into the effect of gradual vitrification on the reactivity of the polymerizable systems, the conversion - dose profiles of the epoxy diacrylate were recorded at various temperatures. The dependence of the limiting conversion on the polymerization temperature was examined under various experimental conditions and compared with the conversion - T g relation, which was deduced from dynamic thermo-mechanical analysis. The correlation between resulting T g measured in the samples at maximal conversion for each curing temperature was shown to be slightly deviating from linearity. A phenomenological model of the reaction kinetics was shown to depict satisfactorily the observed photopolymerization profiles. From the well-determined T g - conversion relation, a semi-mechanistic kinetic model taking into account the gradual vitrification of the network can be foreseen.