The Non-Core Regions of Human Lysozyme Amyloid Fibrils Influence Cytotoxicity

Mossuto, Maria F.; Dhulesia, Anne; Devlin, Glyn L.; Frare, Erica; Kumita, Janet R.; Laureto, Patrizia Polverino de; Dumoulin, Mireille; Fontana, Angelo; Dobson, Christopher M.; Salvatella, Xavier

doi:10.1016/j.jmb.2010.07.005

Cited by 101 publications

(109 citation statements)

References 56 publications

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“…Toxicity can be due to the exposure of normally buried moieties such as hydrophobic side chains or free main chain NH and CO groups that can lead to non-native hydrogen bond interactions with other proteins (Mossuto et al, 2010). Indeed, several studies have shown that sequestration of metastable and essential cellular factors such as proteins involved in chromatin remodeling, transcription, translation, nuclear import and cytoskeletal structure by the aggregates is the major cause of observed toxicity in vivo (Bucciantini et al, 2002;Chai et al, 2002;Olzscha et al, 2011;Suhr et al, 2001).…”

Section: Prion Protein Extracellularmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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Section: Prion Protein Extracellularmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…found to be cytotoxic [3][4][5][6] or to induce the dysfunction of neurons and neuronal loss [7]. The binding of anle138b might inhibit aggregate growth and/or could reduce the toxicity of the aggregates and hamper disease progression as observed in in vivo experiments [16].…”

Section: Tablementioning

confidence: 99%

“…These aggregates, located in the brain of infected individuals, are characterized by a cross-β-sheet protein structure and a fibrillar morphology under the electron microscope. The amyloid aggregates are considered to play an important role in the pathogenesis of neurodegenerative diseases [3][4][5][6][7]. Furthermore, recent experiments pointed out that not only the fibrillar structures but especially the formation of smaller, highly cytotoxic oligomeric forms [8] might lead to neuronal loss [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to α-synuclein aggregates

Deeg

Reiner

Schmidt

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background: Special diphenyl-pyrazole compounds and in particular anle138b were found to reduce the progression of prion and Parkinson's disease in animal models. The therapeutic impact of these compounds was attributed to the modulation of α-synuclein and prion-protein aggregation related to these diseases. Methods: Photophysical and photochemical properties of the diphenyl-pyrazole compounds anle138b, anle186b and sery313b and their interaction with monomeric and aggregated α-synuclein were studied by fluorescence techniques. Results: The fluorescence emission of diphenyl-pyrazole is strongly increased upon incubation with α-synuclein fibrils, while no change in fluorescence emission is found when brought in contact with monomeric α-synuclein. This points to a distinct interaction between diphenyl-pyrazole and the fibrillar structure with a high binding affinity (K d = 190 ± 120 nM) for anle138b. Several α-synuclein proteins form a hydrophobic binding pocket for the diphenyl-pyrazole compound. A UV-induced dehalogenation reaction was observed for anle138b which is modulated by the hydrophobic environment of the fibrils. Conclusion: Fluorescence of the investigated diphenyl-pyrazole compounds strongly increases upon binding to fibrillar α-synuclein structures. Binding at high affinity occurs to hydrophobic pockets in the fibrils. General significance: The observed particular fluorescence properties of the diphenyl-pyrazole molecules open new possibilities for the investigation of the mode of action of these compounds in neurodegenerative diseases. The high binding affinity to aggregates and the strong increase in fluorescence upon binding make the compounds promising fluorescence markers for the analysis of aggregation-dependent epitopes.

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“…In the final steady state or stationary phase, fibrils and monomers are in equilibrium and the structure of the fibrils can still evolve for example by rearrangement of the region of the protein that is not part of the core of the fibrils, leading to mature fibrils [11]. Besides, the amyloid fibrils can also associate laterally [12]. The lag phase can be shortened or even suppressed by the addition of seeds (i.e.…”

Section: Introductionmentioning

confidence: 99%

Camelid single-domain antibody fragments: Uses and prospects to investigate protein misfolding and aggregation, and to treat diseases associated with these phenomena

2015

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Keywords:Variable domain of heavy-chain antibody Inhibition of protein misfolding and aggregation Protein misfolding diseases Amyloidoses V H H Nanobody a b s t r a c tThe deposition of misfolded peptides and proteins in the form of amyloid fibrils is the hallmark of nearly fifty medical disorders, including Alzheimer's disease, Parkinson's disease, prion diseases and type II diabetes. These disorders, referred to as amyloidoses, generally become apparent late in life. Their psycho-sociological and economic incidence in western societies will be therefore considerable in the coming decades due to the ageing of the population. Neither preventing nor curative treatments are available yet. These disorders constitute therefore a medical challenge of great importance. Thus, an extensive research is being carried out to understand, at the molecular level, (i) how amyloidogenic proteins misfold and convert from their soluble form into amyloid fibrils, and (ii) how these aggregates or some of their oligomeric precursor species are toxic. The formation of amyloid fibrils proceeds through a complex nucleation/polymerisation mechanism with the formation of various species, including small oligomers. In this review, we focus on how V H Hs or nanobodies, the antigen-binding domains of camelid heavy-chain antibodies, are being increasingly used to characterise each of the species formed on the pathway of fibril formation in terms of structure, stability, kinetics of formation and toxicity. We first introduce the characteristic features of nanobodies compared to those of conventional antibody fragments. Thereafter, we discuss how nanobodies, due to their unique properties, are used as probes to dissect the molecular mechanisms of misfolding and aggregation of six proteins associated with diseases, i.e. human lysozyme, b2-microglobulin, a-synuclein, prion, polyadenylate binding protein nuclear 1 and amyloid b-peptide. A brief general presentation of each disease and the associated peptide/protein is also provided. In addition, we discuss how nanobodies could be used as early diagnostic tools and as novel strategies to treat diseases associated with protein misfolding and aggregation.© 2015 Elsevier B.V. and Societe Française de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.Abbreviations: Ab, antibody; Ab, amyloid b-peptide; AD, Alzheimer's disease; ANS, anilino naphthalene-sulfonic acid; AP, alkaline phosphatase; APP, amyloid precursor protein; aSyn, a-synuclein; b2m, b2-microglobulin; BBB, bloodebrain barrier; CDR, complementarity determining region; C m , concentration of mid-denaturation; CR, Congo red; CSF, cerebrospinal fluid; DN6b2m, a truncated form of b2m lacking the six N-terminal amino acids; DLS, dynamic light scattering; DRA, dialysis-related amyloidosis; FR, framework; FTIR, Fourier transform infrared spectroscopy; Fv, variable fragment made of the VH and VL domains of conventional antibodies; GFP, green fluorescent protein; HCAb, heavy-chain antibody; H/D, hydrogen/deuterium; HSQC, heteronuclear s...

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The Non-Core Regions of Human Lysozyme Amyloid Fibrils Influence Cytotoxicity

Cited by 101 publications

References 56 publications

Firefly luciferase mutants as sensors of proteome stress

Firefly luciferase mutants as sensors of proteome stress

Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to α-synuclein aggregates

Camelid single-domain antibody fragments: Uses and prospects to investigate protein misfolding and aggregation, and to treat diseases associated with these phenomena

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