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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 11 December 2012, Vol.109(50), pp.20455-60
    Description: Protein misfolding and aggregation cause serious degenerative conditions such as Alzheimer's, Parkinson, and prion diseases. Damage to membranes is thought to be one of the mechanisms underlying cellular toxicity of a range of amyloid assemblies. Previous studies have indicated that amyloid fibrils can cause membrane leakage and elicit cellular damage, and these effects are enhanced by fragmentation of the fibrils. Here we report direct 3D visualization of membrane damage by specific interactions of a lipid bilayer with amyloid-like fibrils formed in vitro from β(2)-microglobulin (β(2)m). Using cryoelectron tomography, we demonstrate that fragmented β(2)m amyloid fibrils interact strongly with liposomes and cause distortions to the membranes. The normally spherical liposomes form pointed teardrop-like shapes with the fibril ends seen in proximity to the pointed regions on the membranes. Moreover, the tomograms indicated that the fibrils extract lipid from the membranes at these points of distortion by removal or blebbing of the outer membrane leaflet. Tiny (15-25 nm) vesicles, presumably formed from the extracted lipids, were observed to be decorating the fibrils. The findings highlight a potential role of fibrils, and particularly fibril ends, in amyloid pathology, and report a previously undescribed class of lipid-protein interactions in membrane remodelling.
    Keywords: Amyloid -- Chemistry
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Biophysical Journal, 17 November 2015, Vol.109(10), pp.1999-2000
    Description: Nucleation is a process that initiates phase transitions. Since the classical work of Gibbs on nucleation thermodynamics at the end of the nineteenth century, research into nucleation processes has been spread into a huge variety of scientific fields. To date, nucleation has been studied in disciplines ranging from biophysics to cosmology in systems spanning atomic to planetary scales and beyond (1). Proteins in solution are also known historically to form a variety of states and structures through nucleation (2, 3). In the past two decades, the assembly of proteins into highly ordered amyloid fibrils associated with numerous human diseases such as Alzheimer’s disease, Parkinson’s disease, and Type II diabetes mellitus has sparked renewed interest in theory development, which has resulted in new kinetic models of protein fibril assembly (4, 5). With these new developments, nucleation has again come to the fore in protein biophysics through the nucleated processes in which supersaturated solutions of proteins form insoluble supramolecular protein aggregates consisting of amyloid fibrils, which are defined by their highly ordered cross-β conformation (6). Thus, amyloid assembly converts soluble proteins into insoluble fractions that can be associated with human diseases, and the nucleation mechanism that initiates this phase transition represents a hitherto unresolved process of medical and fundamental biophysical importance.
    Keywords: Biology
    ISSN: 0006-3495
    E-ISSN: 1542-0086
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  • 3
    Language: English
    In: Biophysical Journal, 17 December 2013, Vol.105(12), pp.2811-2819
    Description: Delineating the nanoscale properties and the dynamic assembly and disassembly behaviors of amyloid fibrils is key for technological applications that use the material properties of amyloid fibrils, as well as for developing treatments of amyloid-associated disease. However, quantitative mechanistic understanding of the complex processes involving these heterogeneous supramolecular systems presents challenges that have yet to be resolved. Here, we develop an approach that is capable of resolving the time dependence of fibril particle concentration, length distribution, and length and position dependence of fibril fragmentation rates using a generic mathematical framework combined with experimental data derived from atomic force microscopy analysis of fibril length distributions. By application to amyloid assembly of -microglobulin in vitro under constant mechanical stirring, we present a full description of the fibril fragmentation and growth behavior, and demonstrate the predictive power of the approach in terms of the samples’ fibril dimensions, fibril load, and their efficiency to seed the growth of new amyloid fibrils. The approach developed offers opportunities to determine, quantify, and predict the course and the consequences of amyloid assembly.
    Keywords: Biology
    ISSN: 0006-3495
    E-ISSN: 1542-0086
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  • 4
    In: Xue, Wei-Feng and Radford, Sheena E. (2013) An Imaging and Systems Modeling Approach to Fibril Breakage Enables Prediction of Amyloid Behavior. Biophysical Journal, 105 (12). pp. 2811-2819.
    Description: Delineating the nanoscale properties and the dynamic assembly and disassembly behaviors of amyloid fibrils is key for technological applications that use the material properties of amyloid fibrils, as well as for developing treatments of amyloid-associated disease. However, quantitative mechanistic understanding of the complex processes involving these heterogeneous supramolecular systems presents challenges that have yet to be resolved. Here, we develop an approach that is capable of resolving the time dependence of fibril particle concentration, length distribution, and length and position dependence of fibril fragmentation rates using a generic mathematical framework combined with experimental data derived from atomic force microscopy analysis of fibril length distributions. By application to amyloid assembly of β2-microglobulin in vitro under constant mechanical stirring, we present a full description of the fibril fragmentation and growth behavior, and demonstrate the predictive power of the approach in terms of the samples’ fibril dimensions, fibril load, and their efficiency to seed the growth of new amyloid fibrils. The approach developed offers opportunities to determine, quantify, and predict the course and the consequences of amyloid assembly.
    Keywords: Q Science ; QC Physics ; QD Chemistry ; QP517 Biochemistry
    ISSN: 0006-3495
    Source: University of Kent
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  • 5
    Language: English
    In: The Journal of Chemical Physics, 07 May 2016, Vol.144(17)
    Description: Self-assembly of proteins into amyloid aggregates is an important biological phenomenon associated with human diseases such as Alzheimer’s disease. Amyloid fibrils also have potential applications in nano-engineering of biomaterials. The kinetics of amyloid assembly show an exponential growth phase preceded by a lag phase, variable in duration as seen in bulk experiments and experiments that mimic the small volumes of cells. Here, to investigate the origins and the properties of the observed variability in the lag phase of amyloid assembly currently not accounted for by deterministic nucleation dependent mechanisms, we formulate a new stochastic minimal model that is capable of describing the characteristics of amyloid growth curves despite its simplicity. We then solve the stochastic differential equations of our model and give mathematical proof of a central limit theorem for the sample growth trajectories of the nucleated aggregation process. These results give an asymptotic description for our simple model, from which closed form analytical results capable of describing and predicting the variability of nucleated amyloid assembly were derived. We also demonstrate the application of our results to inform experiments in a conceptually friendly and clear fashion. Our model offers a new perspective and paves the way for a new and efficient approach on extracting vital information regarding the key initial events of amyloid formation.
    Keywords: Articles
    ISSN: 0021-9606
    E-ISSN: 1089-7690
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  • 6
    In: Eugène, Sarah and Xue, Wei-Feng and Robert, Philippe and Doumic, Marie (2016) Insights into the variability of nucleated amyloid polymerization by a minimalistic model of stochastic protein assembly. The Journal of Chemical Physics, 144 (17). p. 175101.
    Description: Self-assembly of proteins into amyloid aggregates is an important biological phenomenon associated with human diseases such as Alzheimer’s disease. Amyloid brils also have potential applications in nano-engineering of biomaterials. The kinetics of amyloid assembly show an exponential growth phase preceded by a lag phase, variable in duration as seen in bulk experiments and experiments that mimic the small volumes of cells. Here, to investigate the origins and the properties of the observed variability in the lag phase of amyloid assembly currently not accounted for by deterministic nucleation dependent mechanisms, we formulate a new stochastic minimal model that is capable of describing the characteristics of amyloid growth curves despite its simplicity. We then solve the stochastic di erential equations of our model and give mathematical proof of a central limit theorem for the sample growth trajectories of the nucleated aggregation process. These results give an asymptotic description for our simple model, from which closed form analytical results capable of describing and predicting the variability of nucleated amyloid assembly were derived. We also demonstrate the application of our results to inform experiments in a conceptually friendly and clear fashion. Our model o ers a new perspective and paves the way for a new and e cient approach on extracting vital information regarding the key initial events of amyloid formation.
    Keywords: Q Science ; QA Mathematics (inc Computing science) ; QC Physics ; QD Chemistry ; QP517 Biochemistry
    ISSN: 0021-9606
    Source: University of Kent
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  • 7
    In: Sheynis, Tania and Friediger, Anat and Xue, Wei-Feng and Hellewell, Andrew L. and Tipping, Kevin W and Hewitt, Eric W. and Radford, Sheena E. and Jelinek, Raz (2013) Aggregation modulators interfere with membrane interactions of beta2-microglobulin fibrils. Biophysical Journal, 105 (3). pp. 745-755.
    Description: Amyloid fibril accumulation is a pathological hallmark of several devastating disorders, including Alzheimer's disease, prion diseases, type II diabetes, and others. Although the molecular factors responsible for amyloid pathologies have not been deciphered, interactions of misfolded proteins with cell membranes appear to play important roles in these disorders. Despite increasing evidence for the involvement of membranes in amyloid-mediated cytotoxicity, the pursuit for therapeutic strategies has focused on preventing self-assembly of the proteins comprising the amyloid plaques. Here we present an investigation of the impact of fibrillation modulators upon membrane interactions of β2-microglobulin (β2m) fibrils. The experiments reveal that polyphenols (epigallocatechin gallate, bromophenol blue, and resveratrol) and glycosaminoglycans (heparin and heparin disaccharide) differentially affect membrane interactions of β2m fibrils measured by dye-release experiments, fluorescence anisotropy of labeled lipid, and confocal and cryo-electron microscopies. Interestingly, whereas epigallocatechin gallate and heparin prevent membrane damage as judged by these assays, the other compounds tested had little, or no, effect. The results suggest a new dimension to the biological impact of fibrillation modulators that involves interference with membrane interactions of amyloid species, adding to contemporary strategies for combating amyloid diseases that focus on disruption or remodeling of amyloid aggregates.
    Keywords: QC Physics ; QD Chemistry ; QP517 Biochemistry
    ISSN: 0006-3495
    Source: University of Kent
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  • 8
    In: Smith, Rachel A. S. and Abell, Benjamin and Smith, David P. and Nabok, Aleksey and Blakeman, Ben J. F. and Xue, Wei-Feng (2015) Analysis of Toxic Amyloid Fibril Interactions at Natively Derived Membranes by Ellipsometry. PLOS ONE, 10 (7). e0132309.
    Description: There is an ongoing debate regarding the culprits of cytotoxicity associated with amyloid disorders. Although small pre-fibrillar amyloid oligomers have been implicated as the primary toxic species, the fibrillar amyloid material itself can also induce cytotoxicity. To investigate membrane disruption and cytotoxic effects associated with intact and fragmented fibrils, the novel in situ spectroscopic technique of Total Internal Reflection Ellipsometry (TIRE) was used. Fibril lipid interactions were monitored using natively derived whole cell membranes as a model of the in vivo environment. We show that fragmented fibrils have an increased ability to disrupt these natively derived membranes by causing a loss of material from the deposited surface when compared with unfragmented fibrils. This effect was corroborated by observations of membrane disruption in live cells, and by dye release assay using synthetic liposomes. Through these studies we demonstrate the use of TIRE for the analysis of protein-lipid interactions on natively derived lipid surfaces, and provide an explanation on how amyloid fibrils can cause a toxic gain of function, while entangled amyloid plaques exert minimal biological activity.
    Keywords: Q Science
    ISSN: 1932-6203
    Source: University of Kent
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  • 9
    In: Jakhria, Toral and Hellewell, Andrew L. and Porter, Morwenna Y. and Jackson, Matthew P. and Tipping, Kevin W. and Xue, Wei-Feng and Radford, Sheena E. and Hewitt, Eric W. (2014) Beta2-Microglobulin Amyloid Fibrils Are Nanoparticles That Disrupt Lysosomal Membrane Protein Trafficking and Inhibit Protein Degradation by Lysosomes. Journal of Biological Chemistry, 289 (52). pp. 35781-35794.
    Keywords: Q Science ; QP517 Biochemistry
    ISSN: 0021-9258
    Source: University of Kent
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  • 10
    Language: English
    In: PLoS ONE, August 6, 2014, Vol.9(8)
    Description: Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of [beta].sub.2 -microglobulin ([beta].sub.2 m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which [beta].sub.2 m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of [beta].sub.2 m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that [beta].sub.2 m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between [beta].sub.2 m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of [beta].sub.2 m amyloid-associated osteoarticular tissue destruction in DRA.
    Keywords: Surface Active Agents ; Tryptophan ; Fluorescence ; Proteins ; Lipids ; Ph ; Phosphates ; Amyloidosis
    ISSN: 1932-6203
    Source: Cengage Learning, Inc.
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