Sequence-Dependent Conformational Properties of PGGG Motif in Tau Repeats: Insights from Molecular Dynamics Simulations of Narrow Pick Filament

ACS Chemical Neuroscience, Journal Year: 2022, Volume and Issue: 14(1), P. 136 - 147

Published: Dec. 13, 2022

Tauopathies are a class of neurodegenerative diseases correlated with the presence pathological Tau fibrils as diagnostic marker. The microtubule-binding repeat region protein, which includes R1, R2, R3, and R4 repeats, constitutes core these fibrils. Each consists semiconserved C-terminal hexapeptide flanked by KxGS PGGG motifs. Previous studies have shown influence peptides on protein aggregation, yet their repeat-specific properties less explored. Using molecular dynamics, we probed sequence-specific (264ENLKHQ269) in determining compact local conformation R1 narrow Pick filament (NPF) homologous E264G mutation. In addition to that, also studied 262S phosphorylation this is proposed alleviate pathogenesis Pick's disease. Interestingly, determined that mutation induces conformational shift 270PGGG273 from turn random coil. This dependence experimentally verified R1R3-E264G mutant construct, displayed accelerated aggregation compared R1R3 wild-type construct. A significant delay R1R3-G326E further demonstrates importance 326G R3 repeat. Thus, conclude motif repeats strongly dependent sequence hexapeptide.

Language: Английский

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Remediation of Metal Oxide Nanotoxicity with a Functional Amyloid

Advanced Science, Journal Year: 2024, Volume and Issue: 11(23)

Published: April 6, 2024

Abstract Understanding the environmental health and safety of nanomaterials (NanoEHS) is essential for sustained development nanotechnology. Although extensive research over past two decades has elucidated phenomena, mechanisms, implications in cellular organismal models, active remediation adverse biological effects remains largely unexplored. Inspired by recent developments functional amyloids biomedical engineering, this work shows their new utility as metallothionein mimics strategically important area NanoEHS. Specifically, metal ions released from CuO ZnO nanoparticles are sequestered through cysteine coordination electrostatic interactions with beta‐lactoglobulin (bLg) amyloid, revealed inductively coupled plasma mass spectrometry molecular dynamics simulations. The toxicity oxide subsequently mitigated amyloids, validated cell viability apoptosis assays vitro murine survival biomarker vivo. As bLg amyloid fibrils can be readily produced whey large quantities at a low cost, study offers crucial strategy remediating footprints transition nanomaterials.

Language: Английский

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An NMR Toolkit to Probe Amyloid Oligomer Inhibition in Neurodegenerative Diseases: From Ligand Screening to Dissecting Binding Topology and Mechanisms of Action

ChemPlusChem, Journal Year: 2024, Volume and Issue: unknown

Published: May 7, 2024

The aggregation of amyloid peptides and proteins into toxic oligomers is a hallmark neurodegenerative diseases, such as Alzheimer's disease, Parkinson's Machado-Joseph's transmissible spongiform encephalopathies. Inhibition formation interactions with biological counterparts, well the triggering non-toxic amorphous aggregates, are strategies towards preventive interventions against these pathologies. NMR spectroscopy addresses need for structural characterization their binding to inhibitors, rapid screening compound libraries ligand identification. Here we briefly discuss solution experiments constituting spectroscopist's toolkit provide examples application.

Language: Английский

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Proteomic Evidence for Amyloidogenic Cross-Seeding in Fibrinaloid Microclots

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(19), P. 10809 - 10809

Published: Oct. 8, 2024

In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils fibrils exhibiting a cross-β motif parallel or antiparallel β-sheets oriented perpendicular to fibre direction. These can intertwine mature fibres. Similar phenomena occur in blood from individuals circulating inflammatory molecules (and also some originating viruses bacteria). Such pathological clotting result an anomalous termed fibrinaloid microclots. Previous proteomic analyses these microclots have shown presence non-fibrin(ogen) proteins, suggesting more complex mechanism than simple entrapment. We thus provide evidence against such entrapment model, noting that clot pores are too large centrifugation would removed weakly bound proteins. Instead, we explore whether co-aggregation into may involve axial (multiple proteins within same fibril), lateral (single-protein contributing fibre), both types integration. Our analysis data different diseases shows no significant quantitative overlap normal plasma proteome correlation between abundance their Notably, abundant like α-2-macroglobulin, fibronectin, transthyretin absent microclots, while less as adiponectin, periostin, von Willebrand factor well represented. Using bioinformatic tools, including AmyloGram AnuPP, found entrapped exhibit high amyloidogenic tendencies, integration elements structures. This likely contributes microclots’ resistance proteolysis. findings underscore role cross-seeding microclot formation highlight need for further investigation structural properties implications thrombotic diseases. insights foundation developing novel diagnostic therapeutic strategies targeting disorders.

Language: Английский

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Beta-Amyloid and Its Asp7 Isoform: Morphological and Aggregation Properties and Effects of Intracerebroventricular Administration

Brain Sciences, Journal Year: 2024, Volume and Issue: 14(10), P. 1042 - 1042

Published: Oct. 21, 2024

Background/Objectives: One of the hallmarks Alzheimer’s disease (AD) is accumulation aggregated beta-amyloid (Aβ) protein in form senile plaques within brain tissue. Senile contain various post-translational modifications Aβ, including prevalent isomerization Asp7 residue. The isomer has been shown to exhibit increased neurotoxicity and induce amyloidogenesis tissue transgenic mice. toxicity Aβ peptides may be partly mediated by their structure morphology. In this respect, study we analyzed structural aggregation characteristics isoform Aβ42 compared them those synthetic Aβ42. We also investigated effects intracerebroventricular (i.c.v.) administration these peptides, a method often used AD-like symptoms rodent models. Methods: Atomic force microscopy (AFM) was conducted compare morphological properties iso-Aβ42. i.c.v. stereotaxic proteins were assessed via behavioral analysis reactive oxygen species (ROS) estimation vivo using scanning ion-conductance microscope with confocal module. Results: AFM measurements revealed differences between two most notably soluble toxic oligomeric forms. iso-Aβ42 induced spatial memory deficits rats elevated oxidative stress levels vivo, suggesting potential ROS pathogenic mechanism peptide. Conclusions: findings support further investigation translational research on AD suggest its involvement neurodegenerative processes.

Language: Английский

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