Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy

Nature, Journal Year: 2020, Volume and Issue: 578(7794), P. 273 - 277

Published: Feb. 5, 2020

Language: Английский

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Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules

Nature, Journal Year: 2019, Volume and Issue: 568(7752), P. 420 - 423

Published: March 20, 2019

Language: Английский

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Structures of α-synuclein filaments from multiple system atrophy

Nature, Journal Year: 2020, Volume and Issue: 585(7825), P. 464 - 469

Published: May 27, 2020

Language: Английский

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Half a century of amyloids: past, present and future

Chemical Society Reviews, Journal Year: 2020, Volume and Issue: 49(15), P. 5473 - 5509

Published: Jan. 1, 2020

Amyloid diseases are global epidemics with profound health, social and economic implications yet remain without a cure. This dire situation calls for research into the origin pathological manifestations of amyloidosis to stimulate continued development new therapeutics. In basic science engineering, cross-β architecture has been constant thread underlying structural characteristics functional amyloids, realizing that amyloid structures can be both in nature fuelled innovations artificial whose use today ranges from water purification 3D printing. At conclusion half century since Eanes Glenner's seminal study amyloids humans, this review commemorates occasion by documenting major milestones date, perspectives biology, biophysics, medicine, microbiology, engineering nanotechnology. We also discuss challenges opportunities drive interdisciplinary field moving forward.

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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α-Synuclein misfolding and aggregation: Implications in Parkinson’s disease pathogenesis

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Journal Year: 2019, Volume and Issue: 1867(10), P. 890 - 908

Published: March 7, 2019

Language: Английский

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Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles

Molecular Neurodegeneration, Journal Year: 2019, Volume and Issue: 14(1)

Published: July 22, 2019

Alpha-synuclein (αS) is the major constituent of Lewy bodies and a pathogenic hallmark all synucleinopathathies, including Parkinson's disease (PD), dementia with (DLB), multiple system atrophy (MSA). All diseases are determined by αS aggregate deposition but can be separated into distinct pathological phenotypes diagnostic criteria. Here we attempt to reinterpret literature, particularly in terms how structure may relate pathology. We do so context rapidly evolving field, taking account newly revealed structural information on both native forms protein, recent solid state NMR cryoEM fibril structures. discuss these new findings impact current understanding PD, where this direct field.

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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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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α‐synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities

Journal of Neurochemistry, Journal Year: 2019, Volume and Issue: 150(5), P. 522 - 534

Published: June 29, 2019

Abstract This review article provides an overview of the different species that α‐synuclein aggregates can populate. It also attempts to reconcile conflicting views regarding cytotoxic roles oligomers versus fibrils. α‐synuclein, while highly dynamic in monomeric state, access a large number assembly states. Depending on conditions, these states interconvert over timescales. The fibrillar state is most thermodynamically favored due many stabilizing interactions formed between each unit, but types form at rates. end distribution likely reflect kinetic partitioning as much thermodynamic equilibra. In addition, metastable oligomeric species, some which are on‐pathway and others off‐pathway, be populated for remarkably long periods time. Chemical modifications (phosphorylation, oxidation, covalent links ligands, etc.) perturb physical interconversions invariably destabilize leading small prefibrillar assemblies coalesce into amorphous Both have been shown although firm conclusions require very careful evaluation particle concentrations complicated by great variety heterogeneity experimentally observed mechanistic relationship fibrils remains clarified, both terms potential dissolution oligomers. While possibly implicated collapse neuronal homeostasis, state(s) appears efficient propagating itself vitro vivo , pointing critical multiple aggregate progression Parkinson’s disease ( https://onlinelibrary.wiley.com/page/journal/14714159/homepage/virtual_issues.htm ). image part Special Issue “Synuclein”.

Language: Английский

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