ORCID Profile
0000-0002-3168-2679
Current Organisation
Macquarie University
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Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.BRAINRES.2010.12.077
Abstract: The amyloid precursor protein (APP) is known to increase following traumatic brain injury (TBI). This increase in levels of APP may be deleterious to outcome due to the production of neurotoxic Aβ. Conversely, this upregulation may be beneficial as cleavage of APP via the alternative non-amyloidogenic pathway produces the soluble α form of APP (sAPPα), which is known to have many neuroprotective and neurotrophic functions. Indeed it has previously been shown that treatment with sAPPα following a diffuse injury in rats improves outcome. However, the exact location within the sAPPα molecule which contains this neuroprotective activity has yet to be determined. The sAPPα peptide can consist of up to 6 domains, with the main isoform in the brain missing the 4th and 5th. Of the remaining domains, the D1 and D6a domains seem the most likely as they have been shown to have beneficial actions in vitro. This present study examined the effects of in vivo posttraumatic administration via an intracerebroventricular injection of the D1, D2 and D6a domains of sAPPα on outcome following moderate-impact acceleration TBI in rats. While treatment with either the D1 or D6a domains was found to significantly improve motor and cognitive outcome, as assessed on the rotarod and Y maze, treatment with the D2 domain had no effect. Furthermore axonal injury was reduced in D1 and D6a domain treated animals, but not those that received the D2 domain. As the D1 and D6a domains contain a heparin binding region while the D2 domain does not, this suggests that sAPPα mediates its neuroprotective response through its ability to bind to heparin sulfate proteoglycans.
Publisher: Wiley
Date: 19-01-2016
DOI: 10.1111/JNC.13443
Abstract: Amyloid beta (Aβ) peptide is the major constituent of the extracellular amyloid plaques deposited in the brains of Alzheimer's disease patients and is central to the pathogenic pathway causing this disease. The identity of the neurotoxic Aβ species remains elusive. We previously reported that Aβ toxicity correlates strongly with its neuronal cell binding leading us to hypothesize that neuronal cell death is caused by the binding of a specific oligomeric Aβ species. To identify the specific oligomeric Aβ species that is associated with cell death, we treated mouse cortical neuronal cultures with synthetic Aβ40 and Aβ42 peptides and identified that the cellular Aβ binding and neurotoxicity were time and concentration dependent. We found a significant correlation between the amount of trimer and tetramer species bound to neurons with increasing neurotoxicity. We prepared Aβ40 oligomers (up to tetramers) using photo-induced cross-linking of unmodified peptides to confirm this oligomer-specific neurotoxic activity. Our results identify the Aβ tetramer, followed by the trimer, as the most toxic low-order oligomers Aβ species. Our findings suggested that binding of amyloid-β (Aβ) tetramer and trimer, not monomer or dimer, to neurons is critical to induce neuronal cell death associated with Alzheimer's Disease. We proposed that Aβ trimer and tetramer are the potential neurotoxic Aβ species. This would provide more specific therapeutic target for Alzheimer's Disease.
Publisher: Public Library of Science (PLoS)
Date: 10-07-2020
Publisher: Wiley
Date: 10-03-2010
DOI: 10.1016/J.FEBSLET.2010.03.012
Abstract: This study demonstrates that in vitro incubation of isolated rat brain mitochondria with recombinant human alpha-synuclein leads to dose-dependent loss of mitochondrial transmembrane potential and phosphorylation capacity. However, alpha-synuclein does not seem to have any significant effect on the activities of respiratory chain complexes under similar conditions of incubation suggesting that the former may impair mitochondrial bioenergetics by direct effect on mitochondrial membranes. Moreover, the recombinant wild type alpha-synuclein and different mutant forms (A30P, A53T and E46K) have essentially similar effects on rat brain isolated mitochondria. The results are significant in view of the fact that alpha-synucleinopathy is involved in the pathogenesis of Parkinson's disease.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2017
Publisher: Elsevier BV
Date: 02-2021
Publisher: American Chemical Society (ACS)
Date: 25-10-2002
DOI: 10.1021/BI026070V
Abstract: We have investigated the effect of disulfide cross-linking on amyloid formation by human apolipoprotein (apo) C-II. Three derivatives of apoC-II were generated by inserting a cysteine residue on either the N-terminus (C(N)-apoC-II), C-terminus (C(C)-apoC-II), or both termini (C(N)C(C)-apoC-II). Under reducing conditions, all derivatives formed amyloid with a fibrous ribbon morphology similar to that of wild-type apoC-II. Under oxidizing conditions, C(N)- and C(N)C(C)-apoC-II formed a highly tangled network of fibrils, suggesting that the addition of an N-terminal cysteine to apoC-II promotes interfibril disulfide cross-links. Fibrils formed by C(C)-apoC-II under oxidizing conditions were closely packed but less tangled than fibrils formed by the C(N) and C(N)C(C) derivatives. The frequency of closed ring structures was more than doubled for C(C)-apoC-II compared to wild-type apoC-II. The kinetics of fibril formation by all cysteine derivatives was markedly enhanced under oxidizing conditions, suggesting that disulfide cross-linking promotes amyloid formation. Substoichiometric levels of preformed C(N)- and C(C)-apoC-II dimers accelerate amyloid formation by wild-type apoC-II. These data suggest that the N- and C-termini of apoC-II are close together in the amyloid fibril such that covalent cross-linking of either the N or C end of apoC-II promotes nucleation and the "seeding" of fibril growth.
Publisher: Humana Press
Date: 2011
DOI: 10.1007/978-1-60327-223-0_12
Abstract: Analytical ultracentrifugation is a classical technique used to study the solution behavior of proteins. Experimentally determined sedimentation coefficients provide information regarding the size, shape, and interactions of biological macromolecules. Sedimentation velocity methods have been used to characterize the different aggregation states of amyloid oligomers and fibrils. This chapter first describes the theoretical background for sedimentation velocity analysis. It then provides experimental protocols for sedimentation velocity experiments using the analytical ultracentrifuge. Finally, this chapter describes the procedure used to analyze sedimentation velocity data to obtain the size distribution of amyloid fibrils and their oligomeric precursors.
Publisher: Public Library of Science (PLoS)
Date: 13-02-2015
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.FREERADBIOMED.2009.02.009
Abstract: alpha-Synuclein is the major component of the intracellular Lewy body inclusions present in Parkinson disease (PD) neurons. PD involves the loss of dopaminergic neurons in the substantia nigra and the subsequent depletion of dopamine (DA) in the striatum. DA can inhibit alpha-synuclein fibrillization in vitro and promote alpha-synuclein aggregation into soluble oligomers. We have studied the mechanism by which DA mediates alpha-synuclein aggregation into soluble oligomers. Reacting alpha-synuclein with DA increased the mass of alpha-synuclein by 64 Da. NMR showed that all four methionine residues were oxidized by DA, consistent with the addition of 64 Da. Substituting all four methionines to alanine significantly reduced the formation of DA-mediated soluble oligomers. The (125)YEMPS(129) motif in alpha-synuclein can modulate DA inhibition of alpha-synuclein fibrillization. However, alpha-synuclein ending before the (125)YEMPS(129) motif (residues 1-124) could still form soluble oligomers. The addition of exogenous synthetic YEMPS peptide inhibited the formation of soluble oligomers and resulted in the YEMPS peptide being oxidized. Therefore, the (125)YEMPS(129) acts as an antioxidant rather than interacting directly with DA. Our study defines methionine oxidation as the dominant mechanism by which DA generates soluble alpha-synuclein oligomers and highlights the potential role for oxidative stress in modulating alpha-synuclein aggregation.
Publisher: Springer Science and Business Media LLC
Date: 04-05-2016
DOI: 10.1038/SREP25288
Abstract: Rice blast is a devastating disease of rice caused by the fungus Magnaporthe oryzae and can result in loss of a third of the annual global rice harvest. Two hydrophobin proteins, MPG1 and MHP1, are highly expressed during rice blast infections. These hydrophobins have been suggested to facilitate fungal spore adhesion and to direct the action of the enzyme cutinase 2, resulting in penetration of the plant host. Therefore a mechanistic understanding of the self-assembly properties of these hydrophobins and their interaction with cutinase 2 is crucial for the development of novel antifungals. Here we report details of a study of the structure, assembly and interactions of these proteins. We demonstrate that, in vitro , MPG1 assembles spontaneously into amyloid structures while MHP1 forms a non-fibrillar film. The assembly of MPG1 only occurs at a hydrophobic:hydrophilic interface and can be modulated by MHP1 and other factors. We further show that MPG1 assemblies can much more effectively retain cutinase 2 activity on a surface after co-incubation and extensive washing compared with other protein coatings. The assembly and interactions of MPG1 and MHP1 at hydrophobic surfaces thereby provide the basis for a possible mechanism by which the fungus can develop appropriately at the infection interface.
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.JMB.2009.02.007
Abstract: The deposition of alpha-synuclein (alpha-syn) aggregates in dopaminergic neurons is a key feature of Parkinson's disease. While dopamine (DA) can modulate alpha-syn aggregation, it is unclear which other factors can regulate the actions of DA on alpha-syn. In this study, we investigated the effect of solution conditions (buffer, salt and pH) on the oligomerization of alpha-syn by DA. We show that alpha-syn oligomerization is dependent on the oxidation of DA into reactive intermediates. Under acidic pH conditions, DA is stable, and DA-mediated oligomerization of alpha-syn is inhibited. From pH 7.0 to pH 11.0, DA is unstable and undergoes redox reactions, promoting the formation of SDS-resistant soluble oligomers of alpha-syn. We show that the reactive intermediate 5,6-dihydroxylindole mediates the formation of alpha-syn soluble oligomers under physiological conditions (pH 7.4). In contrast, under acidic conditions (pH 4.0), 5,6-dihydroxylindole promotes the formation of SDS-resistant insoluble oligomers that further associate to form sheet-like fibrils with beta-sheet structure that do not bind the dye thioflavin T. These results suggest that distinct reactive intermediates of DA, and not DA itself, interact with alpha-syn to generate the alpha-syn aggregates implicated in Parkinson's disease.
Publisher: Annual Reviews
Date: 20-06-2017
DOI: 10.1146/ANNUREV-BIOCHEM-061516-044847
Abstract: Many critical biological processes take place at hydrophobic:hydrophilic interfaces, and a wide range of organisms produce surface-active proteins and peptides that reduce surface and interfacial tension and mediate growth and development at these boundaries. Microorganisms produce both small lipid–associated peptides and hipathic proteins that allow growth across water:air boundaries, attachment to surfaces, predation, and improved bioavailability of hydrophobic substrates. Higher-order organisms produce surface-active proteins with a wide variety of functions, including the provision of protective foam environments for vulnerable reproductive stages, evaporative cooling, and gas exchange across airway membranes. In general, the biological functions supported by these erse polypeptides require them to have an hipathic nature, and this is achieved by a erse range of molecular structures, with some proteins undergoing significant conformational change or intermolecular association to generate the structures that are surface active.
Publisher: Elsevier BV
Date: 04-2006
Publisher: Elsevier BV
Date: 03-2004
Publisher: Elsevier BV
Date: 12-2019
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.JMB.2006.11.062
Abstract: Protein aggregation underlies an increasing number of human diseases. Recent experiments have shown that the aggregation reaction is exquisitely specific involving particular interactions between non-native proteins. However, aggregation of certain proteins, for ex le beta-amyloid, in vivo leads to the recruitment of other proteins into the aggregate. Antichymotrypsin, a non-fibril forming protein, is always observed to be associated with beta-amyloid plaques in Alzheimer's sufferers. The role of antichymotrypsin is controversial with studies showing it can either accelerate or inhibit the aggregation reaction. To investigate the role of antichymotrypsin in fibrillogenesis we have studied its interaction with apolipoprotein C-II, a well characterized model system for the study of fibrillogenesis. Our data demonstrate that sub-stoichiometric amounts of antichymotrypsin and its alternate structural forms can dramatically accelerate the aggregation of apolipoprotein C-II, whereas the presence of alpha(1)-antitrypsin, a structural homologue of antichymotrypsin, cannot. Sedimentation velocity experiments show more apolipoprotein C-II fibrils were formed in the presence of antichymotrypsin. Using pull-down assays and immuno-gold labeling we demonstrate an interaction between antichymotrypsin and apolipoprotein C-II fibrils that specifically occurs during fibrillogenesis. Taken together these data demonstrate an interaction between antichymotrypsin and apolipoprotein C-II that accelerates fibrillogenesis and indicates a specific role for accessory proteins in protein aggregation.
Publisher: American Chemical Society (ACS)
Date: 22-05-2008
DOI: 10.1021/JA800708X
Abstract: The interaction of the small (140 amino acid) protein, alpha-synuclein (alphaS), with Cu(2+) has been proposed to play a role in Parkinson's disease (PD). While some insight from truncated model complexes has been gained, the nature of the corresponding Cu(2+) binding modes in the full length protein remains comparatively less well characterized. This work examined the Cu(2+) binding of recombinant human alphaS using Electron Paramagnetic Resonance (EPR) spectroscopy. Wild type (wt) alphaS was shown to bind stoichiometric Cu(2+) via two N-terminal binding modes at physiological pH. An H50N mutation isolated one binding mode, whose g parallel, A parallel, and metal-ligand hyperfine parameters correlated well with a {NH2, N(-), beta-COO(-), H2O} mode previously identified in truncated model fragments. Electron spin-echo envelope modulation (ESEEM) studies of wt alphaS confirmed the second binding mode at pH 7.4 involved coordination of His50 and its g parallel and A parallel parameters correlated with either {NH2, N(-), beta-COO(-), N(Im)} or {N(Im), 2 N(-)} coordination observed in alphaS fragments. At pH 5.0, His50-anchored Cu(2+) binding was greatly diminished, while {NH2, N(-), beta-COO(-), H2O} binding persisted in conjunction with another two binding modes. Metal-ligand hyperfine interactions from one of these indicated a 1N3O coordination sphere, which was ascribed to a {NH2, CO} binding mode. The other was characterized by a spectrum similar to that previously observed for diethylpyrocarbonate-treated alphaS and was attributed to C-terminal binding centered on Asp121. In total, four Cu(2+) binding modes were identified within pH 5.0-7.4, providing a more comprehensive picture of the Cu(2+) binding properties of recombinant alphaS.
Publisher: Elsevier BV
Date: 08-2012
Publisher: American Chemical Society (ACS)
Date: 13-04-2007
DOI: 10.1021/BI602554Z
Abstract: Apolipoprotein amyloid deposits and lipid oxidation products are colocalized in human atherosclerotic tissue. In this study we show that the primary ozonolysis product of cholesterol, 3beta-hydroxy-5-oxo-5,6-secocholestan-6-al (KA), rapidly promotes human apolipoprotein (apo) C-II amyloid fibril formation in vitro. Previous studies show that hydrophobic aldehydes, including KA, modify proteins by the formation of a Schiff base with the lysine epsilon-amino group or N-terminal amino group. High-performance liquid chromatography, mass spectrometry, and proteolysis of KA-modified apoC-II revealed that KA randomly modified six different lysine residues, with primarily one KA attached per apoC-II molecule. Competition experiments showed that an aldehyde scavenging compound partially inhibited the ability of KA to hasten apoC-II fibril formation. Conversely, the acid derivative of KA, lacking the ability to form a Schiff base, accelerated apoC-II fibril formation, albeit to a lesser extent, suggesting that amyloidogenesis triggered by KA involves both covalent and noncovalent mechanisms. The viability of a noncovalent mechanism mediated by KA has been observed previously with alpha-synuclein aggregation, implicated in Parkinson's disease. Electron microscopy demonstrated that fibrils formed in the presence of KA had a similar morphology to native fibrils however, the isolated KA-apoC-II covalent adducts in the absence of unmodified apoC-II formed fibrillar structures with altered ropelike morphologies. KA-mediated fibril formation by apoC-II was inhibited by the addition of the amine-containing compound hydralazine and the lipid-binding protein apoA-I. These in vitro studies suggest that the oxidized small molecule pool could trigger or hasten the aggregation of apoC-II to form amyloid deposits.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JMB.2018.07.025
Abstract: Hydrophobins are hiphilic proteins secreted by filamentous fungi in a soluble form, which can self-assemble at hydrophilic/hydrophobic or water/air interfaces to form hiphilic layers that have multiple biological roles. We have investigated the conformational changes that occur upon self-assembly of six hydrophobins that form functional amyloid fibrils with a rodlet morphology. These hydrophobins are present in the cell wall of spores from different fungal species. From available structures and NMR chemical shifts, we established the secondary structures of the monomeric forms of these proteins and monitored their conformational changes upon amyloid rodlet formation or thermal transitions using synchrotron radiation circular dichroism and Fourier-transform infrared spectroscopy (FT-IR). Thermal transitions were followed by synchrotron radiation circular dichroism in quartz cells that allowed for microbubbles and hence water/air interfaces to form and showed irreversible conformations that differed from the rodlet state for most of the proteins. In contrast, thermal transitions on hermetic calcium fluoride cells showed reversible conformational changes. Heating hydrophobin solutions with a water/air interface on a silicon crystal surface in FT-IR experiments resulted in a gain in β-sheet content typical of amyloid fibrils for all except one protein. Rodlet formation was further confirmed by electron microscopy. FT-IR spectra of pre-formed hydrophobin rodlet preparations also showed a gain in β-sheet characteristic of the amyloid cross-β structure. Our results indicate that hydrophobins are capable of significant conformational plasticity and the nature of the assemblies formed by these surface-active proteins is highly dependent on the interface at which self-assembly takes place.
Publisher: MDPI AG
Date: 17-09-2014
DOI: 10.3390/NANO4030827
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.JMB.2010.12.006
Abstract: The self-assembly of specific proteins to form insoluble amyloid fibrils is a characteristic feature of a number of age-related and debilitating diseases. Lipid-free human apolipoprotein C-II (apoC-II) forms characteristic amyloid fibrils and is one of several apolipoproteins that accumulate in amyloid deposits located within atherosclerotic plaques. X-ray diffraction analysis of aligned apoC-II fibrils indicated a simple cross-β-structure composed of two parallel β-sheets. Examination of apoC-II fibrils using transmission electron microscopy, scanning transmission electron microscopy, and atomic force microscopy indicated that the fibrils are flat ribbons composed of one apoC-II molecule per 4.7-Å rise of the cross-β-structure. Cross-linking results using single-cysteine substitution mutants are consistent with a parallel in-register structural model for apoC-II fibrils. Fluorescence resonance energy transfer analysis of apoC-II fibrils labeled with specific fluorophores provided distance constraints for selected donor-acceptor pairs located within the fibrils. These findings were used to develop a simple 'letter-G-like' β-strand-loop-β-strand model for apoC-II fibrils. Fully solvated all-atom molecular dynamics (MD) simulations showed that the model contained a stable cross-β-core with a flexible connecting loop devoid of persistent secondary structure. The time course of the MD simulations revealed that charge clusters in the fibril rearrange to minimize the effects of same-charge interactions inherent in parallel in-register models. Our structural model for apoC-II fibrils suggests that apoC-II monomers fold and self-assemble to form a stable cross-β-scaffold containing relatively unstructured connecting loops.
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.JMB.2007.10.038
Abstract: A common feature of many of the most important and prominent amyloid-forming proteins is their ability to bind lipids and lipid complexes. Lipids are ubiquitous components of disease-associated amyloid plaques and deposits in humans, yet the specific roles of lipid in the process of amyloid fibril formation are poorly understood. This study investigated the effect of phospholipids on amyloid fibril formation by human apolipoprotein (apo) C-II using phosphatidylcholine derivatives comprising acyl chains of up to 14 carbon atoms. Submicellar concentrations of short-chain phospholipids increase the rate of apoC-II fibril formation in an acyl-chain-length- and concentration-dependent fashion, while high micellar concentrations of phospholipids completely inhibited amyloid formation. At lower concentrations of soluble phospholipid complexes, fibril formation by apoC-II was only partially inhibited, and under these conditions, aggregation followed a two-phase process. Electron microscopy showed that the fibrils resulting from the second phase of aggregation were straight, cablelike, and about 13 nm wide, in contrast to the homogeneous twisted-ribbon morphology of apoC-II fibrils formed under lipid-free conditions. Seeding experiments showed that this alternative fibril structure could be templated both in the presence and in the absence of lipid complex, suggesting that the two morphologies result from distinct assembly pathways. Circular dichroism spectroscopy studies indicated that the secondary structural conformation within the straight-type and ribbon-type fibrils were distinct, further suggesting ergent assembly pathways. These studies show that phospholipid complexes can change the structural architecture of mature fibrils and generate new fibril morphologies with the potential to alter the in vivo behaviour of amyloid. Such lipid interactions may play a role in defining the structural features of fibrils formed by erse amyloidogenic proteins.
Publisher: Springer US
Date: 15-10-2020
DOI: 10.1007/978-1-4939-9869-2_4
Abstract: The fungal hydrophobins are small proteins that are able to self-assemble spontaneously into hipathic monolayers at hydrophobic:hydrophilic interfaces. These protein monolayers can reverse the wettability of a surface, making them suitable for increasing the biocompatibility of many hydrophobic nanomaterials. One subgroup of this family, the class I hydrophobins, forms monolayers that are composed of extremely robust amyloid-like fibrils, called rodlets. Here, we describe the protocols for the production and purification of recombinant hydrophobins and oxidative refolding to a biologically active, soluble, monomeric form. We describe methods to trigger the self-assembly into the fibrillar rodlet state and techniques to characterize the physicochemical properties of the polymeric forms.
Publisher: Portland Press Ltd.
Date: 18-08-2014
DOI: 10.1042/BSE0560207
Abstract: Amyloids are insoluble fibrillar protein deposits with an underlying cross-β structure initially discovered in the context of human diseases. However, it is now clear that the same fibrillar structure is used by many organisms, from bacteria to humans, in order to achieve a erse range of biological functions. These functions include structure and protection (e.g. curli and chorion proteins, and insect and spider silk proteins), aiding interface transitions and cell–cell recognition (e.g. chaplins, rodlins and hydrophobins), protein control and storage (e.g. Microcin E492, modulins and PMEL), and epigenetic inheritance and memory [e.g. Sup35, Ure2p, HET-s and CPEB (cytoplasmic polyadenylation element-binding protein)]. As more ex les of functional amyloid come to light, the list of roles associated with functional amyloids has continued to expand. More recently, amyloids have also been implicated in signal transduction [e.g. RIP1/RIP3 (receptor-interacting protein)] and perhaps in host defence [e.g. aDrs (anionic dermaseptin) peptide]. The present chapter discusses in detail functional amyloids that are used in Nature by micro-organisms, non-mammalian animals and mammals, including the biological roles that they play, their molecular composition and how they assemble, as well as the coping strategies that organisms have evolved to avoid the potential toxicity of functional amyloid.
Publisher: Portland Press Ltd.
Date: 10-2013
DOI: 10.1042/BSR20130092
Abstract: The deposition of α-syn (α-synuclein) as amyloid fibrils and the selective loss of DA (dopamine) containing neurons in the substantia nigra are two key features of PD (Parkinson's disease). α-syn is a natively unfolded protein and adopts an α-helical conformation upon binding to lipid membrane. Oligomeric species of α-syn have been proposed to be the pathogenic species associated with PD because they can bind lipid membranes and disrupt membrane integrity. DA is readily oxidized to generate reactive intermediates and ROS (reactive oxygen species) and in the presence of DA, α-syn form of SDS-resistant soluble oligomers. It is postulated that the formation of the α-syn:DA oligomers involves the cross-linking of DA-melanin with α-syn, via covalent linkage, hydrogen and hydrophobic interactions. We investigate the effect of lipids on DA-induced α-syn oligomerization and studied the ability of α-syn:DA oligomers to interact with lipids vesicles. Our results show that the interaction of α-syn with lipids inhibits the formation of DA-induced α-syn oligomers. Moreover, the α-syn:DA oligomer cannot interact with lipid vesicles or cause membrane permeability. Thus, the formation of α-syn:DA oligomers may alter the actions of α-syn which require membrane association, leading to disruption of its normal cellular function.
Publisher: Springer Science and Business Media LLC
Date: 02-05-2019
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.JMB.2007.12.055
Abstract: Alzheimer's and several other diseases are characterized by the misfolding and assembly of protein subunits into amyloid fibrils. Current models propose that amyloid fibril formation proceeds via the self-association of several monomers to form a nucleus, which then elongates by the addition of monomer to form mature fibrils. We have examined the concentration-dependent kinetics of apolipoprotein C-II amyloid fibril formation and correlated this with the final size distribution of the fibrils determined by sedimentation velocity experiments. In contrast to predictions of the nucleation-elongation model, the final size distribution of the fibrils was found to be relatively independent of the starting monomer concentration. To explain these results, we extended the nucleation-elongation model to include fibril breaking and rejoining as integral parts of the amyloid fibril assembly mechanism. The system was examined under conditions that affected the stability of the mature fibrils including the effect of dilution on the free pool of monomeric apolipoprotein C-II and the time-dependent recovery of fibril size following sonication. Antibody-labelling transmission electron microscopy studies provided direct evidence for spontaneous fibril breaking and rejoining. These studies establish the importance of breaking and rejoining in amyloid fibril formation and identify prospective new therapeutic targets in the assembly pathway.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2009
DOI: 10.1007/S11064-009-9986-8
Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by (1) the selective loss of dopaminergic neurons in the substantia nigra and (2) the deposition of misfolded alpha-synuclein (alpha-syn) as amyloid fibrils in the intracellular Lewy bodies in various region of the brain. Current thinking suggests that an interaction between alpha-syn and dopamine (DA) leads to the selective death of neuronal cells and the accumulation of misfolded alpha-syn. However, the exact mechanism by which this occurs is not fully defined. DA oxidation could play a key role is the pathogenesis of PD by causing oxidative stress, mitochondria dysfunction and impairment of protein metabolism. Here, we review the literature on the role of DA and its oxidative intermediates in modulating the aggregation pathways of alpha-syn.
Publisher: MDPI AG
Date: 24-05-2022
DOI: 10.3390/MOLECULES27113382
Abstract: TIR-domain-containing adapter-inducing interferon-β (TRIF) is an innate immune protein that serves as an adaptor for multiple cellular signalling outcomes in the context of infection. TRIF is activated via ligation of Toll-like receptors 3 and 4. One outcome of TRIF-directed signalling is the activation of the programmed cell death pathway necroptosis, which is governed by interactions between proteins that contain a RIP Homotypic Interaction Motif (RHIM). TRIF contains a RHIM sequence and can interact with receptor interacting protein kinases 1 (RIPK1) and 3 (RIPK3) to initiate necroptosis. Here, we demonstrate that the RHIM of TRIF is amyloidogenic and supports the formation of homomeric TRIF-containing fibrils. We show that the core tetrad sequence within the RHIM governs the supramolecular organisation of TRIF amyloid assemblies, although the stable amyloid core of TRIF amyloid fibrils comprises a much larger region than the conserved RHIM only. We provide evidence that RHIMs of TRIF, RIPK1 and RIPK3 interact directly to form heteromeric structures and that these TRIF-containing hetero-assemblies display altered and emergent properties that likely underlie necroptosis signalling in response to Toll-like receptor activation.
Publisher: Elsevier BV
Date: 08-2012
Publisher: Elsevier BV
Date: 04-2023
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Chi Le Lan Pham.