Secondary nucleation in amyloid formation

Chemical Communications, Journal Year: 2018, Volume and Issue: 54(63), P. 8667 - 8684

Published: Jan. 1, 2018

Nucleation of new peptide and protein aggregates on the surfaces amyloid fibrils same or has emerged in past two decades as a major pathway for both generation molecular species responsible cellular toxicity autocatalytic proliferation aggregates. A key question current research is mechanism driving forces governing such processes, known secondary nucleation. In this context, analogies with other self-assembling systems which monomer-dependent nucleation been studied more than century provide valuable source inspiration. Here, we present short overview background then review recent results regarding amyloid-forming peptides proteins, focusing particular β (Aβ) from Alzheimer's disease, some examples α-synuclein Parkinson's disease. Monomer-dependent Aβ was discovered using combination kinetic experiments, global analysis, seeding experiments selective isotope-enrichment, pinpoint monomer origin fibril-catalyzed reaction. Insights into are gained variations solution conditions, temperature sequence. Selective inhibition explored an effective means to limit oligomer production toxicity. We also aimed at finding interaction partners oligomers generated by ongoing aggregation process. At end feature article bring forward outstanding questions testable mechanistic hypotheses formation.

Language: Английский

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Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases

eLife, Journal Year: 2019, Volume and Issue: 8

Published: Feb. 5, 2019

Assembly of microtubule-associated protein tau into filamentous inclusions underlies a range neurodegenerative diseases. Tau filaments adopt different conformations in Alzheimer’s and Pick’s Here, we used cryo- immuno- electron microscopy to characterise that were assembled from recombinant full-length human with four (2N4R) or three (2N3R) microtubule-binding repeats the presence heparin. 2N4R assembles multiple types filaments, structures reveal similar ‘kinked hairpin’ folds, which second third pack against each other. 2N3R are structurally homogeneous, dimeric core, where two molecules parallel manner. The heparin-induced differ those disease, have larger cores repeat compositions. Our results illustrate structural versatility amyloid raise questions about relevance vitro assembly.

Language: Английский

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Amyloid fibril structure of α-synuclein determined by cryo-electron microscopy

Cell Research, Journal Year: 2018, Volume and Issue: 28(9), P. 897 - 903

Published: July 31, 2018

Language: Английский

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Cryo-EM in drug discovery: achievements, limitations and prospects

Nature Reviews Drug Discovery, Journal Year: 2018, Volume and Issue: 17(7), P. 471 - 492

Published: June 8, 2018

Language: Английский

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Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases

Nature Neuroscience, Journal Year: 2018, Volume and Issue: 21(10), P. 1341 - 1349

Published: Sept. 20, 2018

Language: Английский

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Cryo-EM structures of amyloid-β 42 filaments from human brains

Science, Journal Year: 2022, Volume and Issue: 375(6577), P. 167 - 172

Published: Jan. 14, 2022

Hi-res view of human Aβ42 filaments Alzheimer’s disease is characterized by a loss memory and other cognitive functions the filamentous assembly Aβ tau in brain. The peptides into that end at residue 42 central event. Yang et al . used electron cryo–electron microscopy to determine structures from brain (see Perspective Willem Fändrich). They identified two types related S-shaped filaments, each consisting identical protofilaments. These will inform development better vitro animal models, inhibitors assembly, imaging agents with increased specificity sensitivity. —SMH

Language: Английский

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Congo Red and amyloids: history and relationship

Bioscience Reports, Journal Year: 2018, Volume and Issue: 39(1)

Published: Dec. 19, 2018

Staining with Congo Red (CR) is a qualitative method used for the identification of amyloids in vitro and tissue sections. However, drawbacks artefacts obtained when using this dye can be found both vivo Analysis scientific data from previous studies shows that CR staining alone not sufficient confirmation amyloid nature protein aggregates or diagnosis amyloidosis In present paper, we describe characteristics limitations other methods studies. Our historical review on use may provide insight into pitfalls caveats related to technique researchers considering dye.

Language: Английский

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Amyloid Polymorphism in the Protein Folding and Aggregation Energy Landscape

Angewandte Chemie International Edition, Journal Year: 2018, Volume and Issue: 57(28), P. 8370 - 8382

Published: Feb. 15, 2018

Abstract Protein folding involves a large number of steps and conformations in which the protein samples different thermodynamic states characterized by local minima. Kinetically trapped on‐ or off‐pathway intermediates are metastable towards lowest absolute energy minima, have been postulated to be natively folded state where intramolecular interactions dominate, amyloid intermolecular dominate. However, this view largely neglects rich polymorphism found within species. We review landscape recent findings identifying specific transition routes among polymorphs. Observed transitions such as twisted ribbon→crystal helical ribbon→nanotube, forbidden ribbon↛crystal, discussed positioned aggregation landscape. Finally, crystals identified ground

Language: Английский

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Multicomponent peptide assemblies

Chemical Society Reviews, Journal Year: 2018, Volume and Issue: 47(10), P. 3659 - 3720

Published: Jan. 1, 2018

Self-assembled peptide nanostructures have been increasingly exploited as functional materials for applications in biomedicine and energy. The emergent properties of these nanomaterials determine the which they can be exploited. It has recently appreciated that composed multicomponent coassembled peptides often display unique potential to dramatically expand utility peptide-based materials. This review presents recent efforts development assemblies. discussion includes assemblies derived from short low molecular weight peptides, amphiphiles, coiled coil collagen, β-sheet peptides. design, structure, properties, are presented order illustrate formulations sophisticated next-generation bio-inspired

Language: Английский

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Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy

eLife, Journal Year: 2019, Volume and Issue: 8

Published: Dec. 9, 2019

Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson’s disease (PD). Previously, we reported the structure fibrils (residues 1–121), composed two protofibrils that connected via densely-packed interface formed by residues 50–57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report new polymorphic atomic structures termed polymorphs 2a and 2b, at 3.0 Å 3.4 resolution, respectively. These show radically different compared to previously polymorphs. The have 10 nm fibril diameter protofilaments which interact intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 2b). non-amyloid component (NAC) region is fully buried non-described interactions with N-terminus. A hydrophobic cleft, location familial PD mutation sites, nature protofilament now invite formulate hypotheses about formation, growth stability.

Language: Английский

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