scholarly journals Near-Wall Aggregation of Amyloidogenic Aβ 1-40 Peptide: Direct Observation by the FRET

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7590
Author(s):  
Natalia Katina ◽  
Alisa Mikhaylina ◽  
Nelly Ilina ◽  
Irina Eliseeva ◽  
Vitalii Balobanov
Keyword(s):  
Kinetic Data ◽  
Water Glass ◽  
Amyloid Fibrils ◽  
Liquid Solution ◽  
Conformational Transitions ◽  
Self Organization ◽  
Amyloid Formation ◽  
Amyloidogenic Proteins ◽  
Protein Molecules ◽  
Polypeptide Chains

The formation of amyloid fibrils is one of the variants of the self-organization of polypeptide chains. For the amyloid aggregation, the solution must be oversaturated with proteins. The interface of the liquid (solution) and solid (vessel walls) phases can trigger the adsorption of protein molecules, and the resulting oversaturation can initiate conformational transitions in them. In any laboratory experiment, we cannot exclude the presence of surfaces such as the walls of vessels, cuvettes, etc. However, in many works devoted to the study of amyloid formation, this feature is not considered. In our work, we investigated the behavior of the Aβ 1-40 peptide at the water–glass, water–quartz, and water–plastic interface. We carried out a series of simple experiments and showed that the Aβ 1-40 peptide is actively adsorbed on these surfaces, which leads to a significant interaction and aggregation of peptides. This means that the interface can be the place where the first amyloid nucleus appears. We suggest that this effect may also be one of the reasons for the difficulty of reproducing kinetic data when studying the aggregation of the amyloid of the Aβ 1-40 peptide and other amyloidogenic proteins

Inhibition of Amyloid Fibrillation by Small Molecules and Nanomaterials: Strategic Development of Pharmaceuticals Against Amyloidosis

2019 ◽  
Vol 26 (5) ◽  
pp. 315-323 ◽  
Author(s):  
Vandna Sharma ◽  
Kalyan Sundar Ghosh
Keyword(s):  
Small Molecules ◽  
Amyloid Fibrils ◽  
Hydrophobic Interactions ◽  
General Mechanism ◽  
Amyloid Formation ◽  
Strategic Development ◽  
Unfolded Protein ◽  
Protein Molecules ◽  
Amyloid Fibrillation ◽  
Partially Unfolded

Amyloid fibrils are a special class of self-assembled protein molecules, which exhibit various toxic effects in cells. Different physiological disorders such as Alzheimer’s, Parkinson’s, Huntington’s diseases, etc. happen due to amyloid formation and lack of proper cellular mechanism for the removal of fibrils. Therefore, inhibition of amyloid fibrillation will find immense applications to combat the diseases associated with amyloidosis. The development of therapeutics against amyloidosis is definitely challenging and numerous strategies have been followed to find out anti-amyloidogenic molecules. Inhibition of amyloid aggregation of proteins can be achieved either by stabilizing the native conformation or by decreasing the chances of assembly formation by the unfolded/misfolded structures. Various small molecules such as naturally occurring polyphenols, flavonoids, small organic molecules, surfactants, dyes, chaperones, etc. have demonstrated their capability to interrupt the amyloid fibrillation of proteins. In addition to that, in last few years, different nanomaterials were evolved as effective therapeutic inhibitors against amyloidosis. Aromatic and hydrophobic interactions between the partially unfolded protein molecules and the inhibitors had been pointed as a general mechanism for inhibition. In this review article, we are presenting an overview on the inhibition of amyloidosis by using different small molecules (both natural and synthetic origin) as well as nanomaterials for development of pharmaceutical strategies against amyloid diseases.

IS IT POSSIBLE TO PREDICT AMYLOIDOGENIC REGIONS FROM SEQUENCE ALONE?

2006 ◽  
Vol 04 (02) ◽  
pp. 373-388 ◽  
Author(s):  
OXANA V. GALZITSKAYA ◽  
SERGIY O. GARBUZYNSKIY ◽  
MICHAIL YU. LOBANOV
Keyword(s):  
Amino Acid ◽  
Protein Sequence ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Fibril Formation ◽  
Amino Acid Sequences ◽  
Amyloid Formation ◽  
Amyloid Fibril Formation ◽  
Polypeptide Chains ◽  
Proteins And Peptides

Identification of potentially amyloidogenic regions in polypeptide chains is very important because the amyloid fibril formation can be induced in most normal proteins. In our work we suggest a new method to detect amyloidogenic regions in protein sequence. It is based on the assumption that packing is tight inside an amyloid and therefore regions which could potentially pack well would have a tendency to form amyloids. This means that the regions with strong expected packing of residues would be responsible for the amyloid formation. We use this property to identify potentially amyloidogenic regions in proteins basing on their amino acid sequences only. Our predictions are consistent with known disease-related amyloidogenic regions for 8 of 11 amyloid-forming proteins and peptides in which the positions of amyloidogenic regions have been revealed experimentally. Predictions of the regions which are responsible for the formation of amyloid fibrils in proteins unrelated to disease have been also done.

scholarly journals Apomorphine Targets the Pleiotropic Bacterial Regulator Hfq

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 257
Author(s):  
Florian Turbant ◽  
David Partouche ◽  
Omar El Hamoui ◽  
Sylvain Trépout ◽  
Théa Legoubey ◽  
...  
Keyword(s):  
Small Rnas ◽  
Antibacterial Agents ◽  
Amyloid Fibrils ◽  
Noncoding Rnas ◽  
Amyloid Formation ◽  
Gram Negative Bacteria ◽  
Translation Efficiency ◽  
Gram Negative ◽  
Bacterial Adaptation ◽  
E Coli

Hfq is a bacterial regulator with key roles in gene expression. The protein notably regulates translation efficiency and RNA decay in Gram-negative bacteria, thanks to its binding to small regulatory noncoding RNAs. This property is of primary importance for bacterial adaptation and survival in hosts. Small RNAs and Hfq are, for instance, involved in the response to antibiotics. Previous work has shown that the E. coli Hfq C-terminal region (Hfq-CTR) self-assembles into an amyloid structure. It was also demonstrated that the green tea compound EpiGallo Catechin Gallate (EGCG) binds to Hfq-CTR amyloid fibrils and remodels them into nonamyloid structures. Thus, compounds that target the amyloid region of Hfq may be used as antibacterial agents. Here, we show that another compound that inhibits amyloid formation, apomorphine, may also serve as a new antibacterial. Our results provide an alternative in order to repurpose apomorphine, commonly used in the treatment of Parkinson’s disease, as an antibiotic to block bacterial adaptation to treat infections.

scholarly journals Deletion of Serf2 shifts amyloid conformation in an Aβ amyloid mouse model

2021 ◽  
Author(s):  
E. Stroo ◽  
L. Janssen ◽  
O. Sin ◽  
W. Hogewerf ◽  
M. Koster ◽  
...  
Keyword(s):  
Mouse Model ◽  
Amyloid Fibrils ◽  
Mammalian Brain ◽  
Amyloid Formation ◽  
List Type ◽  
Lung Maturation ◽  
Disease Manifestation ◽  
Aβ Amyloid ◽  
Perinatal Lethality

AbstractNeurodegenerative diseases like Alzheimer, Parkinson and Huntington disease are characterized by aggregation-prone proteins that form amyloid fibrils through a nucleation process. Despite the shared β-sheet structure, recent research has shown that structurally different polymorphs exist within fibrils of the same protein. These polymorphs are associated with varying levels of toxicity and different disease phenotypes. MOAG-4 and its human orthologs SERF1 and SERF2 have previously been shown to modify the nucleation and drive amyloid formation and protein toxicity in vitro and in C. elegans. To further explore these findings, we generated a Serf2 knockout (KO) mouse model and crossed it with the APPPS1 mouse model for Aβ amyloid pathology. Full-body KO of Serf2 resulted in a developmental delay and perinatal lethality due to insufficient lung maturation. Therefore, we proceeded with a brain-specific Serf2 KO, which was found to be viable. We examined the Aβ pathology at 1 and 3 months of age, which is before and after the start of amyloid deposition. We show that SERF2 deficiency does not affect the production and overall Aβ levels. Serf2 KO-APPPS1 mice displayed an increased intracellular Aβ accumulation at 1 month and a higher number of Aβ deposits compared to APPPS1 mice with similar Aβ levels. Moreover, conformation-specific dyes and electron microscopy revealed a difference in the structure and amyloid content of these Aβ deposits. Together, our results reveal that SERF2 causes a structural shift in Aβ aggregation in a mammalian brain. These findings indicate that a single endogenous factor may contribute to amyloid polymorphisms, allowing for new insights into this phenomenon’s contribution to disease manifestation.HighlightsLoss of SERF2 slows embryonic development and causes perinatal lethalitySERF2 affects proliferation in a cell-autonomous fashionBrain-specific Serf2 knockout does not affect viability or Aβ productionBrain deletion of Serf2 shifts the amyloid conformation of Aβ

Protein Molecules as Natural Nano Bio Devices: Mobility Analysis

2010 ◽  
Author(s):  
Zahra Shahbazi ◽  
Horea T. Ilies¸ ◽  
Kazem Kazerounian
Keyword(s):  
Degrees Of Freedom ◽  
Conformational Transitions ◽  
Living Cells ◽  
Mobility Analysis ◽  
Folding Process ◽  
Kinematic Chains ◽  
Protein Molecules ◽  
Kinematic Models ◽  
Lower Mobility ◽  
Molecular Components

Proteins are nature’s nano-robots in the form of functional molecular components of living cells. The function of these natural nano-robots often requires conformational transitions between two or more native conformations that are made possible by the intrinsic mobility of the proteins. Understanding these transitions is essential to the understanding of how proteins function, as well as to the ability to design and manipulate protein-based nano-mechanical systems [1]. Modeling protein molecules as kinematic chains provides the foundation for developing powerful approaches to the design, manipulation and fabrication of peptide based molecules and devices. Nevertheless, these models possess a high number of degrees of freedom (DOF) with considerable computational implications. On the other hand, real protein molecules appear to exhibits a much lower mobility during the folding process than what is suggested by existing kinematic models. The key contributor to the lower mobility of real proteins is the formation of Hydrogen bonds during the folding process.

Abstract 539: Soluble Oxidized Apolipoprotein A-I, a Precursor of Amyloid Fibrils, Activates Secretion of Inflammatory Cytokines in Macrophages

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Andrzej Witkowski ◽  
Gary K Chan ◽  
Nancy J Li ◽  
Rui Lu ◽  
Shinji Yokoyama ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Amyloid Fibrils ◽  
Mouse Bone Marrow ◽  
Amyloid Formation ◽  
Cellular Cholesterol ◽  
Atherosclerosis Progression ◽  
Apolipoprotein A ◽  
Inflammatory Protein ◽  
Release Capacity

Atherosclerosis is often described as an inflammatory disease of the arteries. One mechanism whereby apolipoprotein A-I (apoA-I) exerts its anti-atherosclerotic effect is by mitigating the inflammatory response of cells involved in atherosclerosis progression. However, oxidation transforms apoA-I from an anti-inflammatory to a pro-inflammatory protein. We previously reported that oxidation can also promote apoA-I aggregation and formation of amyloid fibrils. In this study, we investigated the mechanistic interplay between oxidation, amyloid formation and the inflammatory response of macrophages to apoA-I. We hypothesized that amyloid fibrils constituted of oxidized apoA-I activate production of inflammatory cytokines in macrophages. To test this hypothesis, amyloidogenic apoA-I was generated by oxidation with an excess of H 2 O 2 (H 2 O 2 -ApoA-I). Intracellular and secreted levels of IL-1β were determined upon incubation of mouse bone marrow derived macrophages (BMDM) with intact-apoA-I, soluble H 2 O 2 -ApoA-I and pre-formed H 2 O 2 -ApoA-I amyloid fibrils. Cellular cholesterol release from RAW264.7 cells was also measured. Soluble H 2 O 2 -ApoA-I (amyloid precursor) retained the cellular cholesterol release capacity of intact-ApoA-I. In BMDM incubated with soluble H 2 O 2 -ApoA-I however, levels of IL-1β synthesis and secretion were at least 2-fold higher than those induced by intact-ApoA-I. In contrast, incubation with H 2 O 2 -ApoA-I amyloid fibrils did not increase the levels of IL-1β synthesis and secretion, compared to intact-ApoA-I. Thus, soluble and functional oxidized apoA-I activates inflammatory cytokine synthesis and secretion in macrophages. Notably, this pro-inflammatory potential was completely neutralized when oxidized apoA-I was aggregated in amyloids. Therefore in atherosclerotic lesions, amyloid formation could reduce, rather than exacerbate, the inflammatory burden produced by pro-inflammatory soluble oxidized apoA-I species.

scholarly journals Synaptic vesicle mimics affect the aggregation of wild-type and A53T α-synuclein variants differently albeit similar membrane affinity

2019 ◽  
Vol 32 (2) ◽  
pp. 59-66
Author(s):  
Sandra Rocha ◽  
Ranjeet Kumar ◽  
Istvan Horvath ◽  
Pernilla Wittung-Stafshede
Keyword(s):  
Synaptic Vesicles ◽  
Amyloid Fibrils ◽  
Membrane Surface ◽  
Amyloid Formation ◽  
Wild Type ◽  
Membrane Affinity ◽  
Axis Parallel ◽  
Biophysical Techniques ◽  
Small Unilamellar Vesicles ◽  
The Brain

Abstract α-Synuclein misfolding results in the accumulation of amyloid fibrils in Parkinson’s disease. Missense protein mutations (e.g. A53T) have been linked to early onset disease. Although α-synuclein interacts with synaptic vesicles in the brain, it is not clear what role they play in the protein aggregation process. Here, we compare the effect of small unilamellar vesicles (lipid composition similar to synaptic vesicles) on wild-type (WT) and A53T α-synuclein aggregation. Using biophysical techniques, we reveal that binding affinity to the vesicles is similar for the two proteins, and both interact with the helix long axis parallel to the membrane surface. Still, the vesicles affect the aggregation of the variants differently: effects on secondary processes such as fragmentation dominate for WT, whereas for A53T, fibril elongation is mostly affected. We speculate that vesicle interactions with aggregate intermediate species, in addition to monomer binding, vary between WT and A53T, resulting in different consequences for amyloid formation.

Sol-Gel Preparation of HAp-Coated Silica Macrospheres from Water Glass and their Protein Adsorption

2012 ◽  
Vol 529-530 ◽  
pp. 637-640
Author(s):  
Jie Li ◽  
Yuki Shirosaki ◽  
Satoshi Hayakawa ◽  
Artemis Stamboulis ◽  
Akiyoshi Osaka
Keyword(s):  
Water Glass ◽  
Electrostatic Interactions ◽  
Coating Layer ◽  
Sol Gel ◽  
Adsorption Model ◽  
Silica Source ◽  
Layer Adsorption ◽  
Protein Molecules ◽  
Gel Preparation ◽  
Ca Alginate

Silica gel macrospheres of 2~4 mm in size, and wrapped with Ca-alginate chelate film were prepared as the substrate for hydroxyapatite coating layer, using water glass as the silica source. Those Ca-SiO2 macrospheres were soaked in a 1:1 (volume) mixture of ethanol and 0.1 M Na2HPO4 to deposit hydroxyapatite layer (HAp-SiO2 macrospheres). Adsorption of bovine serum albumin and egg lysozyme on those Ca-SiO2 and HAp-SiO2 macrospheres under physiological pH (7.2) was well correlated to the Langmuir-type adsorption equation. The electrostatic interactions between the protein molecules and those macrospheres well interpret the adsorption isotherms, while the mesopores in the Ca-SiO2 contributed to some extent. A multi-layer adsorption model was proposed.

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