scholarly journals Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases

2010 ◽  
Vol 12 ◽  
Author(s):  
Jacques Fantini ◽  
Nouara Yahi
Keyword(s):  
Neurodegenerative Diseases ◽  
Conformational Changes ◽  
Amyloid Fibrils ◽  
Fine Tuning ◽  
Neural Cells ◽  
Amyloidogenic Proteins ◽  
Innovative Therapies ◽  
Conformational Plasticity ◽  
Direct Binding ◽  
Α Helix

Alzheimer, Parkinson and other neurodegenerative diseases involve a series of brain proteins, referred to as ‘amyloidogenic proteins’, with exceptional conformational plasticity and a high propensity for self-aggregation. Although the mechanisms by which amyloidogenic proteins kill neural cells are not fully understood, a common feature is the concentration of unstructured amyloidogenic monomers on bidimensional membrane lattices. Membrane-bound monomers undergo a series of lipid-dependent conformational changes, leading to the formation of oligomers of varying toxicity rich in β-sheet structures (annular pores, amyloid fibrils) or in α-helix structures (transmembrane channels). Condensed membrane nano- or microdomains formed by sphingolipids and cholesterol are privileged sites for the binding and oligomerisation of amyloidogenic proteins. By controlling the balance between unstructured monomers and α or β conformers (the chaperone effect), sphingolipids can either inhibit or stimulate the oligomerisation of amyloidogenic proteins. Cholesterol has a dual role: regulation of protein–sphingolipid interactions through a fine tuning of sphingolipid conformation (indirect effect), and facilitation of pore (or channel) formation through direct binding to amyloidogenic proteins. Deciphering this complex network of molecular interactions in the context of age- and disease-related evolution of brain lipid expression will help understanding of how amyloidogenic proteins induce neural toxicity and will stimulate the development of innovative therapies for neurodegenerative diseases.

Conformational changes in the third PDZ domain of the neuronal postsynaptic density protein 95

2019 ◽  
Vol 75 (4) ◽  
pp. 381-391 ◽  
Author(s):  
Ana Camara-Artigas ◽  
Javier Murciano-Calles ◽  
Jose C. Martínez
Keyword(s):  
Binding Site ◽  
Conformational Changes ◽  
Pdz Domain ◽  
Postsynaptic Density ◽  
Crystal Form ◽  
Space Groups ◽  
The Third ◽  
Conformational Plasticity ◽  
Α Helix ◽  
Postsynaptic Density Protein

PDZ domains are protein–protein recognition modules that interact with other proteins through short sequences at the carboxyl terminus. These domains are structurally characterized by a conserved fold composed of six β-strands and two α-helices. The third PDZ domain of the neuronal postsynaptic density protein 95 has an additional α-helix (α3), the role of which is not well known. In previous structures, a succinimide was identified in the β2–β3 loop instead of Asp332. The presence of this modified residue results in conformational changes in α3. In this work, crystallographic structures of the following have been solved: a truncated form of the third PDZ domain of the neuronal postsynaptic density protein 95 from which α3 has been removed, D332P and D332G variants of the protein, and a new crystal form of this domain showing the binding of Asp332 to the carboxylate-binding site of a symmetry-related molecule. Crystals of the wild type and variants were obtained in different space groups, which reflects the conformational plasticity of the domain. Indeed, the overall analysis of these structures suggests that the conformation of the β2–β3 loop is correlated with the fold acquired by α3. The alternate conformation of the β2–β3 loop affects the electrostatics of the carboxylate-binding site and might modulate the binding of different PDZ-binding motifs.

scholarly journals Nigella Sativa : A Potential Inhibitor for Insulin Fibril Formation

2020 ◽  
Vol 11 (1) ◽  
pp. 765-774
Author(s):  
Sandhya A ◽  
Gomathi Kanayiram ◽  
Kiruthika L ◽  
Aafreen Afroz S
Keyword(s):  
Neurodegenerative Diseases ◽  
Conformational Changes ◽  
Type Ii Diabetes ◽  
Amyloid Fibrils ◽  
Nigella Sativa ◽  
Fibril Formation ◽  
Order Structure ◽  
Type Ii ◽  
Aggregation Assay ◽  
Insulin Fibrils

The high order structure from proteins which are self-assembled are known as fibrils. They are collectively called as amyloid fibrils, which generally lead to neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, Type II diabetes. Insulin fibril aggregation is identified to be the major cause of neurodegenerative diseases. The effect of Nigella sativa extract is analyzed based on the fibril inhibition process. The formed fibrils is reduced with the concentration increase of Nigella sativa extract. Insulin fibril is found in Type II diabetes patients after repeated insulin injections subcutaneously. Insulin fibrils are formed in organisms or humans irrespective of their places like hips, shoulder, hands and abdomen. These are evident from the anti-aggregation assay. Thioflavin T (ThT) fluroscence and congo red (CR) assay confirms the inhibition of insulin fibril in the presence of Nigella sativa (NS) extract. Further, inhibition of fibril was confirmed by Scanning Electron Microscope (SEM), where no insulin fibrils was detected whose secondary conformational changes are studied using Fourier Transform Infrared spectroscopy (FT-IR). It is confirmed that insulin fibril inhibition depends on the various concentration of Nigella sativa. Based on the results obtained, it is demonstrated that Nigella sativa extract inhibits the fibril formation and it also provides a therapeutic strategy to prevent insulin fibril formation.

scholarly journals Amyloids: Regulators of Metal Homeostasis in the Synapse

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1441 ◽  
Author(s):  
Masahiro Kawahara ◽  
Midori Kato-Negishi ◽  
Ken-ichiro Tanaka
Keyword(s):  
Neurodegenerative Diseases ◽  
Conformational Changes ◽  
Critical Role ◽  
Lewy Body Disease ◽  
Metal Homeostasis ◽  
Amyloidogenic Proteins ◽  
Neurodegenerative Process ◽  
Amyloid Oligomers ◽  
Associated Proteins ◽  
Regulatory Functions

Conformational changes in amyloidogenic proteins, such as β-amyloid protein, prion proteins, and α-synuclein, play a critical role in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease, prion disease, and Lewy body disease. The disease-associated proteins possess several common characteristics, including the ability to form amyloid oligomers with β-pleated sheet structure, as well as cytotoxicity, although they differ in amino acid sequence. Interestingly, these amyloidogenic proteins all possess the ability to bind trace metals, can regulate metal homeostasis, and are co-localized at the synapse, where metals are abundantly present. In this review, we discuss the physiological roles of these amyloidogenic proteins in metal homeostasis, and we propose hypothetical models of their pathogenetic role in the neurodegenerative process as the loss of normal metal regulatory functions of amyloidogenic proteins. Notably, these amyloidogenic proteins have the capacity to form Ca2+-permeable pores in membranes, suggestive of a toxic gain of function. Therefore, we focus on their potential role in the disruption of Ca2+ homeostasis in amyloid-associated neurodegenerative diseases.

scholarly journals Do carbon nanotubes inhibit or promote amyloid fibrils formation?

2019 ◽  
Keyword(s):  
Carbon Nanotubes ◽  
Conformational Analysis ◽  
Conformational Changes ◽  
Room Temperature ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Ph Values ◽  
Egg White Lysozyme ◽  
Characteristic Features ◽  
Α Helix

Objectives: The purpose of the work was to study the effect of carbon nanotubes on the formation of fibril structures in lysozyme at room temperature under different pH values. Materials and methods: For the preparation of the samples, hen egg-white lysozyme protein (HEWL, Fluka), as well as single-walled (SWCNT, Sigma-Aldrich) and multi-walled (MWCNT, OOO TM “Spetsmash”, Kyiv, Ukraine) carbon nanotubes were used. Used techniques: IR-Fourier Absorption Spectroscopy; confocal microscopy. Results: In this paper, the study of molecular mechanisms of interaction of lysozyme with carbon nanotubes by vibrational spectroscopy was carried out and a conformational analysis of the formed complexes was performed. It is shown that carbon nanotubes can affect the structure of lysozyme even at room temperature and normal pH values, as evidenced by conformational changes in lysozyme due to interaction with carbon nanotubes. Complexes which are formed as a result of such interaction, have characteristic features of amyloid fibrillar structures. It reveals one of possible mechanisms of carbon nanotubes cytotoxicity. On the other hand, such a technique can be introduced to obtain model amyloid fibrils for further study. Conclusion: The method of vibtarional spectroscopy has shown that carbon nanotubes can influence the structure of lysozyme, as it is shown by the conformational analysis of the absorption band Amide I. After the interaction of lysozyme with CNT, an increase in the contribution of antiparallel β-conformation in the structure of lysozyme is observed, and the contribution of the α-helix conformation is reduced, which are characteristic features in the formation of fibrillar structures. The possibility of amyloid fibril formation without the use of high temperatures at different pH values with the interaction of lysozyme and carbon nanotubes, which can be applied as a method for obtaining the model amyloid fibrils, is shown.

Conformational Changes of the Wild-Type hIAPP and the S20P Mutant in Water Revealed by Molecular Dynamics Simulations

2011 ◽  
Vol 396-398 ◽  
pp. 1554-1557
Author(s):  
Mian Wang ◽  
Jian Yi Wang
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Conformational Changes ◽  
Amyloid Fibrils ◽  
Helical Structure ◽  
Wild Type ◽  
Hydrogen Bond Interaction ◽  
Hydrogen Bond Networks ◽  
Α Helix ◽  
Dynamics Simulations

Conformational changes of wild-type (WT) hIAPP and the S20P mutant in explicit water are investigated using molecular dynamics. In the whole simulation, WT shows compacter structure and has more hydrogen-bond networks than S20P. The residues 14-18 in WT is always maintained as a helical structure which is stabilized by the hydrogen bond between Ser20 and NH group of His18, and the other regions in WT partially loosen from α-helix structures into the coil structures. The S20P mutant in a shortage of hydrogen-bond interaction unfolds faster than WT. This work provides insight into the specific conformation of IAPP which is associated with the generation of amyloid fibrils.

scholarly journals Methylene blue inhibits nucleation and elongation of SOD1 amyloid fibrils

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9719
Author(s):  
Greta Musteikyte ◽  
Mantas Ziaunys ◽  
Vytautas Smirnovas
Keyword(s):  
Methylene Blue ◽  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Late Onset ◽  
Amyloid Aggregation ◽  
Amyloidogenic Proteins ◽  
Lateral Sclerosis

Protein aggregation into highly-structured amyloid fibrils is linked to several neurodegenerative diseases. Such fibril formation by superoxide dismutase I (SOD1) is considered to be related to amyotrophic lateral sclerosis, a late-onset and fatal disorder. Despite much effort and the discovery of numerous anti-amyloid compounds, no effective cure or treatment is currently available. Methylene blue (MB), a phenothiazine dye, has been shown to modulate the aggregation of multiple amyloidogenic proteins. In this work we show its ability to inhibit both the spontaneous amyloid aggregation of SOD1 as well as elongation of preformed fibrils.

Current Challenges and Limitations in the Studies of Intrinsically Disordered Proteins in Neurodegenerative Diseases by Computer Simulations

2020 ◽  
Vol 17 ◽  
Author(s):  
Ibrahim Yagiz Akbayrak ◽  
Sule Irem Caglayan ◽  
Zilan Ozcan ◽  
Vladimir N. Uversky ◽  
Orkid Coskuner-Weber
Keyword(s):  
Neurodegenerative Diseases ◽  
Computer Simulations ◽  
Conformational Changes ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Computational Studies ◽  
Accurate Data ◽  
Aggregation Propensity ◽  
Intrinsically Disordered ◽  
Future Developments

: Experiments face challenges in the analysis of intrinsically disordered proteins in solution due to fast conformational changes and enhanced aggregation propensity. Computational studies complement experiments, being widely used in the analyses of intrinsically disordered proteins, especially those positioned at the centers of neurodegenerative diseases. However, recent investigations – including our own – revealed that computer simulations face significant challenges and limitations themselves. In this review, we introduced and discussed some of the scientific challenges and limitations of computational studies conducted on intrinsically disordered proteins. We also outlined the importance of future developments in the areas of computational chemistry and computational physics that would be needed for generating more accurate data for intrinsically disordered proteins from computer simulations. Additional theoretical strategies that can be developed are discussed herein.

scholarly journals Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases

2021 ◽  
Vol 22 (15) ◽  
pp. 8196
Author(s):  
Dorit Trudler ◽  
Swagata Ghatak ◽  
Stuart A. Lipton
Keyword(s):  
Drug Discovery ◽  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Neural Function ◽  
Neural Cells ◽  
Human Samples ◽  
Healthy Donors ◽  
Induced Pluripotent

Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.

scholarly journals Protein Binding Partners of Dysregulated miRNAs in Parkinson’s Disease Serum

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 791
Author(s):  
Wolfgang P. Ruf ◽  
Axel Freischmidt ◽  
Veselin Grozdanov ◽  
Valerie Roth ◽  
Sarah J. Brockmann ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Binding ◽  
Neurodegenerative Diseases ◽  
Extracellular Vesicles ◽  
Abundance Pattern ◽  
Binding Partners ◽  
Direct Binding ◽  
Unsupervised Approach ◽  
High Degree

Accumulating evidence suggests that microRNAs (miRNAs) are a contributing factor to neurodegenerative diseases. Although altered miRNA profiles in serum or plasma have been reported for several neurodegenerative diseases, little is known about the interaction between dysregulated miRNAs and their protein binding partners. We found significant alterations of the miRNA abundance pattern in serum and in isolated serum-derived extracellular vesicles of Parkinson’s disease (PD) patients. The differential expression of miRNA in PD patients was more robust in serum than in isolated extracellular vesicles and could separate PD patients from healthy controls in an unsupervised approach to a high degree. We identified a novel protein interaction partner for the strongly dysregulated hsa-mir-4745-5p. Our study provides further evidence for the involvement of miRNAs and HNF4a in PD. The demonstration that miRNA-protein binding might mediate the pathologic effects of HNF4a both by direct binding to it and by binding to proteins regulated by it suggests a complex role for miRNAs in pathology beyond the dysregulation of transcription.

scholarly journals Polarity-active NIR probes with strong two-photon absorption and ultrahigh binding affinity of insulin amyloid fibrils

2021 ◽  
Author(s):  
Li Li ◽  
Zheng Lv ◽  
Zhongwei Man ◽  
Zhenzhen Xu ◽  
YuLing Wei ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Binding Affinity ◽  
Fluorescent Probes ◽  
Amyloid Fibrils ◽  
Photon Absorption ◽  
Two Photon Absorption ◽  
Two Photon ◽  
Medical Diagnostic

Amyloid fibrils are associated with many neurodegenerative diseases. In-situ and in-vivo visualization of amyloid fibrils is important for medical diagnostic and requires fluorescent probes with both excitation and emission wavelengths in...

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