Biomarkers for neurodegenerative diseases

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(6), P. 954 - 963

Published: June 1, 2021

Language: Английский

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Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(4), P. 2545 - 2647

Published: Feb. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Language: Английский

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Dynamics of oligomer populations formed during the aggregation of Alzheimer’s Aβ42 peptide

Nature Chemistry, Journal Year: 2020, Volume and Issue: 12(5), P. 445 - 451

Published: April 13, 2020

Language: Английский

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Amyloid structures: much more than just a cross-β fold

Current Opinion in Structural Biology, Journal Year: 2019, Volume and Issue: 60, P. 7 - 16

Published: Nov. 3, 2019

In recent years our understanding of amyloid structure has been revolutionised by innovations in cryo-electron microscopy, electron diffraction and solid-state NMR. These techniques have yielded high-resolution structures fibrils isolated from patients with neurodegenerative disease, as well those formed amyloidogenic proteins vitro. The results not only show the expected cross-β structure, but also reveal that fold is unexpectedly diverse complex. Here, we discuss this diversity, highlighting dynamic regions, ligand binding motifs, cavities, non-protein components, structural polymorphism. Collectively, these variations combine to allow generic be realised three dimensions different ways, diversity may related roles disease.

Language: Английский

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Structure and Aggregation Mechanisms in Amyloids

Molecules, Journal Year: 2020, Volume and Issue: 25(5), P. 1195 - 1195

Published: March 6, 2020

The aggregation of a polypeptide chain into amyloid fibrils and their accumulation deposition insoluble plaques intracellular inclusions is the hallmark several misfolding diseases known as amyloidoses. Alzheimer's, Parkinson's Huntington's are some approximately 50 described to date. identification characterization molecular species critical for formation disease development have been focus intense scrutiny. Methods such X-ray electron diffraction, solid-state nuclear magnetic resonance spectroscopy (ssNMR) cryo-electron microscopy (cryo-EM) extensively used they contributed shed new light onto structure amyloid, revealing multiplicity polymorphic structures that generally fit cross-β motif. rational therapeutic approaches against these debilitating increasingly frequent requires thorough understanding mechanisms underlying cascade. Here, we review current knowledge on fibril proteins peptides from kinetic thermodynamic point view, involved in amyloidogenic process, origin cytotoxicity.

Language: Английский

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Simulation Studies of Amyloidogenic Polypeptides and Their Aggregates

Chemical Reviews, Journal Year: 2019, Volume and Issue: 119(12), P. 6956 - 6993

Published: April 11, 2019

Amyloids, fibrillar assembly of (poly)peptide chains, are associated with neurodegenerative illnesses such as Alzheimer's and Parkinson's diseases, for which there no cures. The molecular mechanisms the formation toxic species still elusive. Some peptides proteins can form functional amyloid-like aggregates mainly in bacteria fungi but also humans. Little is known on differences self-assembly pathogenic (poly)peptides. We review atomistic coarse-grained simulation studies amyloid their monomeric, oligomeric, states. Particular emphasis given to challenges one faces characterize at atomic level detail conformational space disordered (poly)peptides aggregation. discuss difficulties comparing results experimental data, we propose new shed light aggregation processes diseases.

Language: Английский

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Extracellular protein components of amyloid plaques and their roles in Alzheimer’s disease pathology

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Aug. 28, 2021

Abstract Alzheimer’s disease (AD) is pathologically defined by the presence of fibrillar amyloid β (Aβ) peptide in extracellular senile plaques and tau filaments intracellular neurofibrillary tangles. Extensive research has focused on understanding assembly mechanisms neurotoxic effects Aβ during last decades but still we only have a brief associated biological processes. This review highlights many other constituents that, beside Aβ, are accumulated plaques, with focus proteins. All living organisms rely delicate network protein functionality. Deposition significant amounts certain proteins insoluble inclusions will unquestionably lead to disturbances network, which may contribute AD copathology. paper provide comprehensive overview that been shown interact discussion their potential roles pathology. Methods can expand knowledge about how incorporated described. Top-down methods analyze post-mortem tissue bottom-up approaches molecular insights organization plaque-like particles compared. Finally, analysis Aβ-interacting partners enriched functional structural key words presented.

Language: Английский

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The Amyloid Phenomenon and Its Significance in Biology and Medicine

Cold Spring Harbor Perspectives in Biology, Journal Year: 2019, Volume and Issue: 12(2), P. a033878 - a033878

Published: April 1, 2019

Christopher M. Dobson, Tuomas P.J. Knowles and Michele Vendruscolo Centre for Misfolding Diseases, Department of Chemistry, University Cambridge, Cambridge CB2 1EW, United Kingdom Correspondence: cmd44{at}cam.ac.uk; tpjk2{at}cam.ac.uk; mv245{at}cam.ac.uk

Language: Английский

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Condensates formed by prion-like low-complexity domains have small-world network structures and interfaces defined by expanded conformations

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Dec. 13, 2022

Abstract Biomolecular condensates form via coupled associative and segregative phase transitions of multivalent macromolecules. Phase separation to percolation is one example such transitions. Here, we characterize molecular mesoscale structural descriptions formed by intrinsically disordered prion-like low complexity domains (PLCDs). These systems conform sticker-and-spacers architectures. Stickers are cohesive motifs that drive interactions through reversible crosslinking spacers affect the cooperativity overall macromolecular solubility. Our computations reproduce experimentally measured sequence-specific behaviors PLCDs. Within simulated condensates, networks inter-sticker crosslinks organize PLCDs into small-world topologies. The dimensions vary with spatial location, being most expanded at preferring be oriented perpendicular interface. results demonstrate even simple type macromolecule feature inhomogeneous organizations molecules interfacial features likely prime them for biochemical activity.

Language: Английский

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Secondary nucleation and elongation occur at different sites on Alzheimer’s amyloid-β aggregates

Science Advances, Journal Year: 2019, Volume and Issue: 5(4)

Published: April 5, 2019

Chaperone regulation of individual microscopic events in Aβ42 aggregation reveals the nature active sites on amyloid fibrils.

Language: Английский

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