α-Synuclein aggregation nucleates through liquid–liquid phase separation

Nature Chemistry, Journal Year: 2020, Volume and Issue: 12(8), P. 705 - 716

Published: June 8, 2020

Language: Английский

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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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Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: Aug. 31, 2018

α-Synuclein (aSyn) fibrillar polymorphs have distinct in vitro and vivo seeding activities, contributing differently to synucleinopathies. Despite numerous prior attempts, how polymorphic aSyn fibrils differ atomic structure remains elusive. Here, we present fibril from the full-length recombinant human their capacity cytotoxicity vitro. By cryo-electron microscopy helical reconstruction, determine structures of two predominant species, a rod twister, both at 3.7 Å resolution. Our models reveal that share kernel bent β-arch, but inter-protofilament interfaces. Thus, different packing same gives rise polymorphs. Analyses disease-related familial mutations suggest potential contribution pathogenesis synucleinopathies by altering population distribution Drug design targeting amyloid neurodegenerative diseases should consider formation concurrent

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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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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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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