Unraveling the Structure and Dynamics of Ac-PHF6-NH2 Tau Segment Oligomers DOI Creative Commons
Iuliia Stroganova, Zenon Toprakcioglu,

Hannah Willenberg

et al.

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 30, 2024

The aggregation of the proteins tau and amyloid-β is a salient feature Alzheimer's disease, most common form neurodegenerative disorders. Upon aggregation, transition from their soluble, monomeric, functional state into insoluble, fibrillar deposits through complex process involving variety intermediate species different morphologies, including monomers, toxic oligomers, insoluble fibrils. To control direct peptide complete characterization all present an understanding molecular processes along pathway are essential. However, this extremely challenging due to transient nature oligomers complexity reaction networks. Therefore, we have employed combined approach that allows us probe structure kinetics oligomeric species, following them over time as they structures. Targeting protein segment Ac-PHF6-NH

Language: Английский

Amyloid formation as a protein phase transition DOI
Thomas C. T. Michaels, Daoyuan Qian, Anđela Šarić

et al.

Nature Reviews Physics, Journal Year: 2023, Volume and Issue: 5(7), P. 379 - 397

Published: June 27, 2023

Language: Английский

Citations

87
Structural evolution of fibril polymorphs during amyloid assembly DOI Creative Commons
Martin Wilkinson, Yong Xu, Dev Thacker

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(26), P. 5798 - 5811.e26

Published: Dec. 1, 2023

Cryoelectron microscopy (cryo-EM) has provided unprecedented insights into amyloid fibril structures, including those associated with disease. However, these structures represent the endpoints of long assembly processes, and their relationship to fibrils formed early in is unknown. Consequently, whether different architectures, potentially pathological properties, form during remains Here, we used cryo-EM determine at times vitro fibrillation a disease-related variant human islet polypeptide (IAPP-S20G). Strikingly, lag, growth, plateau phases have new forms appearing others disappearing as proceeds. A time course wild-type hIAPP also shows changing time, suggesting that this general property IAPP assembly. The observation transiently populated implications for understanding mechanisms potential progression

Language: Английский

Citations

40
Metal–BODIPY complexes: versatile photosensitizers for oxidizing amyloid-β peptides and modulating their aggregation profiles DOI
Mingeun Kim, Gajendra Gupta, Junseong Lee

et al.

Inorganic Chemistry Frontiers, Journal Year: 2024, Volume and Issue: 11(7), P. 1966 - 1977

Published: Jan. 1, 2024

Metal–BODIPY complexes, rationally designed as photosensitizers, can effectively oxidize amyloidogenic peptides upon photoactivation at a relatively longer wavelength, resulting in altering their aggregation profiles.

Language: Английский

Citations

10
Computational Investigation of Coaggregation and Cross-Seeding between Aβ and hIAPP Underpinning the Cross-Talk in Alzheimer’s Disease and Type 2 Diabetes DOI

Xinjie Fan,

Xiaohan Zhang,

Jiajia Yan

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(13), P. 5303 - 5316

Published: June 26, 2024

The coexistence of amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) in the brain pancreas is associated with an increased risk Alzheimer's disease (AD) type 2 diabetes (T2D) due to their coaggregation cross-seeding. Despite this, molecular mechanisms underlying interaction remain elusive. Here, we systematically investigated cross-talk between Aβ hIAPP using atomistic discrete dynamics (DMD) simulations. Our results revealed that amyloidogenic core regions both (Aβ

Language: Английский

Citations

10
Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection DOI
Linwei Yang, Jingwei Zhang, James S. Andon

et al.

Nature Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Language: Английский

Citations

1
Role of conformational dynamics in pathogenic protein aggregation DOI Creative Commons
Xun Sun, H. Jane Dyson, Peter E. Wright

et al.

Current Opinion in Chemical Biology, Journal Year: 2023, Volume and Issue: 73, P. 102280 - 102280

Published: March 4, 2023

Language: Английский

Citations

16
AI-designed NMR spectroscopy RF pulses for fast acquisition at high and ultra-high magnetic fields DOI Creative Commons

V. S. Manu,

Cristina Olivieri, Gianluigi Veglia

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 12, 2023

Abstract Nuclear magnetic resonance (NMR) spectroscopy is a powerful high-resolution tool for characterizing biomacromolecular structure, dynamics, and interactions. However, the lengthy longitudinal relaxation of nuclear spins significantly extends total experimental time, especially at high ultra-high field strengths. Although relaxation-enhanced techniques have sped up data acquisition, their application has been limited by chemical shift dispersion. Here we combined an evolutionary algorithm artificial intelligence to design 1 H 15 N radio frequency (RF) pulses with variable phase amplitude that cover broader bandwidths allow rapid acquisition. We re-engineered basic transverse optimized experiment showed RF shapes enhance spectral sensitivity well-folded proteins 180 kDa molecular weight. These can be tailored re-design triple-resonance experiments accelerating NMR biomacromolecules fields.

Language: Английский

Citations

15
Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease DOI Creative Commons
Justine M. Grixti, Chrispian W. Theron, J. Enrique Salcedo-Sora

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 7, 2024

Abstract Nattokinase, from the Japanese fermented food natto, is a protease with fibrinolytic activity that can thus degrade conventional blood clots. In some cases, however, including in Long COVID, fibrinogen polymerise into an anomalous amyloid form to create clots are resistant normal fibrinolysis and we refer as fibrinaloid microclots. These be detected fluorogenic stain thioflavin T. We describe automated microscopic technique for quantification of microclot formation, which also allows kinetics their formation aggregation recorded. here show recombinant nattokinase effective at degrading microclots vitro . This adds otherwise largely anecdotal evidence, review, might anticipated have value part therapeutic treatments individuals COVID related disorders involve

Language: Английский

Citations

6
Fluorescence-Based Monitoring of Early-Stage Aggregation of Amyloid-β, Amylin Peptide, Tau, and α-Synuclein Proteins DOI Creative Commons
Yuanjie Li, Saurabh Awasthi, Louise C. Bryan

et al.

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(17), P. 3113 - 3123

Published: Aug. 16, 2024

Early-stage aggregates of amyloid-forming proteins, specifically soluble oligomers, are implicated in neurodegenerative diseases such as Alzheimer's disease, Parkinson's and Huntington's disease. Protein aggregation is typically monitored by fluorescence using the amyloid-binding fluorophore thioflavin T (ThT). Thioflavin interacts, however, preferentially with fibrillar amyloid structures rather than soluble, early-stage aggregates. In contrast, two fluorophores, aminonaphthalene 2-cyanoacrylate-spiropyran (AN-SP) triazole-containing boron-dipyrromethene (taBODIPY), were reported to bind amyloidogenic proteins. The present study compares ThT AN-SP taBODIPY regard their ability monitor early stages four different including amyloid-β (Aβ), tau protein, amylin, α-synuclein. results show that three fluorophores vary suitability For instance, presence Aβ intensity increased at an earlier stage ThT, albeit only a small increase case AN-SP. ThT. Finally, α-synuclein could be fluorescence; neither nor showed significant over course These demonstrate formation from specific proteins aggregation, although moderate increases intensity, relatively large uncertainties values, limited solubility both limit usefulness for some capability might accelerate discovery inhibitors minimize toxic oligomeric species potential therapeutic use.

Language: Английский

Citations

6
Exploring the Curvature-Dependence of Boron Nitride Nanoparticles on the Inhibition of hIAPP Aggregation DOI
Rituparna Roy, Sandip Paul

The Journal of Physical Chemistry B, Journal Year: 2023, Volume and Issue: 127(35), P. 7558 - 7570

Published: Aug. 24, 2023

Nanoparticles, particularly carbon nanoparticles, have gathered significant interest in the field of anti-aggregation research. However, due to their cytotoxicity, exploration biocompatible nanoparticles has become a new frontier quest for drugs against human amyloid diseases. The application non-cytotoxic and boron nitride (BN) aggregation been probed tackle this issue. BN displayed inhibitory activity Aβ α-syn peptides. In work, effect on dimerization hIAPP, which is associated with pathogenesis type 2 diabetes, studied. prevent misfolding hIAPP into β-sheet-rich aggregates. On varying curvature, display variation interaction preference hIAPP. Interestingly, as hydrophobicity increases from (5,5) nanotube nanosheet, propensity shifts N-terminal prone C-terminal hydrophobic aromatic stacking interactions are contributing factor toward binding between BN. Due this, flat surface nanosheet shows better potential compared nanotubes. Further, can also disassemble preformed fibrils, more pronounced nanosheet. This study provides insight mechanism by an understanding significance curvature peptides, valuable design antiamyloid drugs.

Language: Английский

Citations

13