Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Dumoulin, Mireille; Dobson, Christopher M.

doi:10.1016/j.biochi.2004.09.012

Cited by 45 publications

(64 citation statements)

References 117 publications

(165 reference statements)

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“…Thus several therapeutic approaches targeting these phenomena are being considered including: (i) reducing the expression level of the amyloidogenic protein, (ii) increasing the clearance of the misfolded amyloidogenic proteins, (iii) increasing the stability of the properly folded amyloidogenic proteins, (iv) neutralising the cytotoxic species, and/or (v) inhibiting or reversing the aggregation of misfolded proteins into oligomers and fibrils. A large body of studies, in addition to those described in the previous section, carried out both in vitro and in animal models has shown that antibodies or antibody fragments can, at least, mediate the last three effects [21,163,168] and improve the cognitive deficit [163,169]. Despite these promising results obtained in the laboratory, clinical trials involving active (i.e.…”

Section: Prospects For Diagnostic and Therapeutic Applicationsmentioning

confidence: 99%

“…For example, the binding properties of a series of antibodies specifically raised against various epitopes at the surface of the native state of a protein can be compared before and after the conformational changes leading successively to amyloidogenic intermediates, oligomeric species and mature fibrils [21,22]. In this way, the regions of the protein that are structurally reorganised can be identified at each step.…”

Section: Introductionmentioning

confidence: 99%

“…Alternatively, partial unfolding events expose to the solvent some regions of the protein, normally buried within the native fold; antibodies raised against such epitopes will therefore recognise amyloidogenic intermediates but not the native conformation of the protein. Thus, such an approach can provide information on the structure which is adopted by the region(s) of the protein involved in the unfolding event [21]. Finally, antibodies recognising epitopes that are generic of oligomeric species or amyloid fibrils have also been described [23e26].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Prospects For Diagnostic and Therapeutic Applicationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Phage peptide consensus sequences were determined using the program CONSENSUS A, C, D, G, N, P, S, T, V) (31), and each uppercase letter represents the particular amino acid. (33) for phage peptides (closed bars) relative to those of the Len (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) peptide (open bars). Each sequence position average hydropathicity value was determined from the sum of residue hydropathicity values divided by the number of total residues.…”

Section: Generation Of Pan-lc Fibril-reactive Antibodies Using the A1mentioning

confidence: 99%

Phage Display and Peptide Mapping of an Immunoglobulin Light Chain Fibril-Related Conformational Epitope

et al. 2007

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Amyloid fibrils and partially unfolded intermediates can be distinguished serologically from native amyloidogenic precursor proteins or peptides. In this regard, we previously had reported that mAb 11-1F4, generated by immunizing mice with a thermally denatured variable domain (V L ) fragment of the human κ4 Bence Jones protein Len, bound to a non-native conformational epitope located within the N-terminal 18 residues of fibrillar, as well as partially denatured, Ig light chains (O'Nuallain B. et al. (2006) Biochemistry 46, 1240. To define further the antibody binding site, we used random peptide phage display and epitope mapping of V L Len using wild-type and alaninemutated Len peptides where it was shown that the antibody epitope was reliant on up to 10 of the first 15 residues of protein Len. Comparison of V κ and V λ N-terminal germline consensus sequences with protein Len and 11-1F4-binding phages indicated that this antibody's cross-reactivity with light chains was related to an invariant proline at position(s) 7 and/or 8, bulky hydrophobic residues at positions 11 and 13, and additionally, to the ability to accommodate amino acid diversity at positions 1-4. Sequence alignments of the phage peptides revealed a central proline, often flanked by aromatic residues. Taken together, these results have provided evidence for the structural basis of the specificity of 11-1F4 for both κ and λ light chain fibrils. We posit that the associated binding site involves a rare type VI β-turn or touch-turn that is anchored by a cis-proline residue. The identification of an 11-1F4-related mimotope should facilitate development of pan-light chain fibril-reactive antibodies that could be used in the diagnosis and treatment of patients with AL amyloidosis.The amyloidoses are a group of over 20 protein misfolding disorders associated with often fatal sporadic and hereditary disorders, including Alzheimer's disease, type II diabetes, and primary (AL) amyloidosis (1-4). All types of amyloid, regardless of amino acid sequence, share tertiary structural and tinctorial features, i.e., they are formed from fibrils composed of extended β-sheets oriented perpendicularly to the long fibril axis (5,6) and bind the dyes thioflavin T and Congo red (7,8). Additionally, fibrils, as well as their assembly intermediates, contain generic conformational epitopes not present on the native proteins (9-16). These common characteristics reflect a similar fibrillogenic pathway(s) involving the assembly of soluble higher-order intermediates into fibrils that are structurally dissimilar to their precursors (2, 13,17).

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“…L'agré-gat responsable de la toxicité cellulaire n'est pas identifié avec certitude. Les différentes structures peuvent être reconnues par des anticorps spécifiques de chaque étape [33] : certains anticorps reconnaissent d'ailleurs des épitopes communs à des oligomères de protéines amyloïdes différentes, en accord avec l'hypothèse d'une structure spatiale commune à ces agrégats [34]. L'immunologie ne se limite pas à l'aide au diagnostic (immuno-histochimie) et à la dissection des mécanismes de la maladie, mais pourrait participer à la thérapeutique [35].…”

Section: Intermédiaire Amylogèneunclassified

Les amyloses, un modèle de maladie du repliement des protéines

2005

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Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Cited by 45 publications

References 117 publications

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

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

Phage Display and Peptide Mapping of an Immunoglobulin Light Chain Fibril-Related Conformational Epitope

Les amyloses, un modèle de maladie du repliement des protéines

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