Anti-amyloidogenic effect of artemin on α-synuclein

2019 ◽  
Vol 0 (0) ◽  
Author(s):  
Narges Marvastizadeh ◽  
Bahareh Dabirmanesh ◽  
Reza H. Sajedi ◽  
Khosro Khajeh
Keyword(s):  
Secondary Structure ◽  
Molecular Chaperone ◽  
Molecular Chaperones ◽  
Neurological Disorders ◽  
Fibril Formation ◽  
Ros Production ◽  
Native Form ◽  
Tht Fluorescence ◽  
A Cell ◽  
Pathogenic Process

Abstract α-Synuclein fibrillation is now regarded as a major pathogenic process in Parkinson’s disease and its proteinaceous deposits are also detected in other neurological disorders including Alzheimer's disease. Therefore anti-amyloidegenic compounds may delay or prevent the progression of synucleinopathies disease. Molecular chaperones are group of proteins which mediate correct folding of proteins by preventing unsuitable interactions which may lead to aggregation. The objective of this study was to investigate the anti-amyloidogenic effect of molecular chaperone artemin on α-synuclein. As the concentration of artemin was increased up to 4 μg/ml, a decrease in fibril formation of α-synuclein was observed using ThT fluorescence and congo red assay. TEM images also demonstrated a reduction in fibrils in the presence of artemin. The secondary structure of α-synuclein was similar to its native form prior to fibrillation when incubated with artemin. A cell-based assay has shown that artemin inhibits α-synuclein aggregation and reduce cytoxicity, apotosis and ROS production. Our results revealed that artemin has efficient chaperon activity for preventing α-synuclein fibril formation and toxicity.

Anti-amyloidogenic effect of artemin on α-synuclein

2020 ◽  
Vol 401 (10) ◽  
pp. 1143-1151
Author(s):  
Narges Marvastizadeh ◽  
Bahareh Dabirmanesh ◽  
Reza H. Sajedi ◽  
Khosro Khajeh
Keyword(s):  
Molecular Chaperone ◽  
Molecular Chaperones ◽  
Neurological Disorders ◽  
Fibril Formation ◽  
Oxygen Species ◽  
Native Form ◽  
Transmission Electron ◽  
Tht Fluorescence ◽  
A Cell ◽  
Pathogenic Process

Abstractα-Synuclein fibrillation is now regarded as a major pathogenic process in Parkinson’s disease and its proteinaceous deposits are also detected in other neurological disorders including Alzheimer's disease. Therefore anti-amyloidegenic compounds may delay or prevent the progression of synucleinopathies disease. Molecular chaperones are group of proteins which mediate correct folding of proteins by preventing unsuitable interactions which may lead to aggregation. The objective of this study was to investigate the anti-amyloidogenic effect of molecular chaperone artemin on α-synuclein. As the concentration of artemin was increased up to 4 μg/ml, a decrease in fibril formation of α-synuclein was observed using thioflavin T (ThT) fluorescence and congo red (CR) assay. Transmission electron microscopy (TEM) images also demonstrated a reduction in fibrils in the presence of artemin. The secondary structure of α-synuclein was similar to its native form prior to fibrillation when incubated with artemin. A cell-based assay has shown that artemin inhibits α-synuclein aggregation and reduce cytotoxicity, apoptosis and reactive oxygen species (ROS) production. Our results revealed that artemin has efficient chaperon activity for preventing α-synuclein fibril formation and toxicity.

scholarly journals HPD degradation regulated by the TTC36-STK33-PELI1 signaling axis induces tyrosinemia and neurological damage

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yajun Xie ◽  
Xiaoyan Lv ◽  
Dongsheng Ni ◽  
Jianing Liu ◽  
Yanxia Hu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Learning And Memory ◽  
Molecular Chaperone ◽  
Neurological Disorders ◽  
Hippocampal Neurons ◽  
Neurological Damage ◽  
Fha Domain ◽  
Signaling Axis ◽  
Tyrosine Metabolism ◽  
Key Enzyme

Abstract Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. Conversely, deficiency or depletion of TTC36 results in enhanced STK33-mediated HPD T382 phosphorylation and binding of PELI1 to HPD and subsequent PELI1-mediated HPD downregulation. Ttc36−/− mice have reduced HPD expression in the liver and exhibit tyrosinemia, damage to hippocampal neurons, and deficits of learning and memory. These findings reveal a previously unknown regulation of HPD expression and highlight the physiological significance of TTC36-STK33-PELI1-regulated HPD expression in tyrosinemia and tyrosinemia-associated neurological disorders.

scholarly journals A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH

2019 ◽  
Vol 294 (29) ◽  
pp. 11259-11275 ◽  
Author(s):  
Mitsuharu Ueda ◽  
Masamitsu Okada ◽  
Mineyuki Mizuguchi ◽  
Barbara Kluve-Beckerman ◽  
Kyosuke Kanenawa ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Amyloid Fibril ◽  
Screening Method ◽  
Fibril Formation ◽  
Neutral Ph ◽  
Amyloid Fibril Formation ◽  
A Cell

Biodiversity as a source of new pharmacophores: A new theory of memory III

2005 ◽  
Vol 77 (1) ◽  
pp. 75-81 ◽  
Author(s):  
◽  
M. Iqbal Choudhary
Keyword(s):  
Natural Products ◽  
Anticancer Agents ◽  
Neurological Disorders ◽  
In Vitro Bioassay ◽  
Natural Sources ◽  
Chemical Basis ◽  
Antioxidant Agents ◽  
A Cell ◽  
The Brain

Several classes of natural products with significant inhibitory activity against target enzymes involved in several diseases have been identified. Spectrophotometer and high-throughput assays were used to assess the inhibition of prolyl endopeptidase (PEP), which led us to some novel inhibitors having potential as anticancer agents. Inhibition of cholinesterase enzymes has led to the discovery of new inhibitors with potential for use in Alzheimer’s disease and other neurological disorders. We have also discovered several potent antioxidant agents from natural sources by using a battery of antioxidant assays. Anti-inflammatory activity of a number of natural products was assayed through a cell-based in vitro bioassay. This article also contains a section on a slightly different topic of chemical basis of memory as presented during the lecture. The theory of the chemical basis of memory based on hydrogen bonding in the brain is further elaborated.

Comparison of Hsc70 orthologs from polar and temperate notothenioid fishes: differences in prevention of aggregation and refolding of denatured proteins

2005 ◽  
Vol 288 (5) ◽  
pp. R1195-R1202 ◽  
Author(s):  
Sean P. Place ◽  
Gretchen E. Hofmann
Keyword(s):  
Molecular Chaperone ◽  
Molecular Chaperones ◽  
Temperate Species ◽  
Effect Of Temperature ◽  
In Vitro Assays ◽  
Comparative Approach ◽  
Antarctic Species ◽  
Temperature Selection ◽  
Lower Temperature

Although a great deal is known about the cellular function of molecular chaperones in general, very little is known about the effect of temperature selection on the function of molecular chaperones in nonmodel organisms. One major unanswered question is whether orthologous variants of a molecular chaperone from differential thermally adapted species vary in their thermal responses. To address this issue, we utilized a comparative approach to examine the temperature interactions of a major cytosolic molecular chaperone, Hsc70, from differently thermally adapted notothenioids. Using in vitro assays, we measured the ability of Hsc70 to prevent thermal aggregation of lactate dehydrogenase (LDH). We further compared the capacity of Hsc70 to refold chemically denatured LDH over the temperature range of −2 to +45°C. Hsc70 purified from the temperate species exhibited greater ability to prevent the thermal denaturation of LDH at 55°C compared with Hsc70 from the cold-adapted species. Furthermore, Hsc70 from the Antarctic species lost the ability to competently refold chemically denatured LDH at a lower temperature compared with Hsc70 from the temperate species. These data indicate the function of Hsc70 in notothenioid fishes maps onto their thermal history and that temperature selection has acted on these molecular chaperones.

Role of calreticulin in the sensitivity of myocardiac H9c2 cells to oxidative stress caused by hydrogen peroxide

2006 ◽  
Vol 290 (1) ◽  
pp. C208-C221 ◽  
Author(s):  
Yoshito Ihara ◽  
Yoshishige Urata ◽  
Shinji Goto ◽  
Takahito Kondo
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Molecular Chaperone ◽  
Vital Role ◽  
H9c2 Cells ◽  
Cardiac Physiology ◽  
Caspase 12 ◽  
A Cell ◽  
Induced Apoptosis

Calreticulin (CRT), a Ca2+-binding molecular chaperone in the endoplasmic reticulum, plays a vital role in cardiac physiology and pathology. Oxidative stress is a main cause of myocardiac apoptosis in the ischemic heart, but the function of CRT under oxidative stress is not fully understood. In the present study, the effect of overexpression of CRT on susceptibility to apoptosis under oxidative stress was examined using myocardiac H9c2 cells transfected with the CRT gene. Under oxidative stress due to H2O2, the CRT-overexpressing cells were highly susceptible to apoptosis compared with controls. In the overexpressing cells, the levels of cytoplasmic free Ca2+ ([Ca2+]i) were significantly increased by H2O2, whereas in controls, only a slight increase was observed. The H2O2-induced apoptosis was enhanced by the increase in [Ca2+]i caused by thapsigargin in control cells but was suppressed by BAPTA-AM, a cell-permeable Ca2+ chelator in the CRT-overexpressing cells, indicating the importance of the level of [Ca2+]i in the sensitivity to H2O2-induced apoptosis. Suppression of CRT by the introduction of the antisense cDNA of CRT enhanced cytoprotection against oxidative stress compared with controls. Furthermore, we found that the levels of activity of calpain and caspase-12 were elevated through the regulation of [Ca2+]i in the CRT-overexpressing cells treated with H2O2 compared with controls. Thus we conclude that the level of CRT regulates the sensitivity to apoptosis under oxidative stress due to H2O2 through a change in Ca2+ homeostasis and the regulation of the Ca2+-calpain-caspase-12 pathway in myocardiac cells.

scholarly journals Translation from the Ribosome to the Clinic: Implication in Neurological Disorders and New Perspectives from Recent Advances

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 680 ◽  
Author(s):  
Hui ◽  
Chen ◽  
Endo ◽  
Tanaka
Keyword(s):  
Neurological Disorders ◽  
Translational Regulation ◽  
De Novo ◽  
Ribosome Profiling ◽  
The Right ◽  
The Brain ◽  
De Novo Protein Synthesis ◽  
Pathogenic Process ◽  
Liquid Liquid Phase Separation ◽  
Better Than

De novo protein synthesis by the ribosome and its multitude of co-factors must occur in a tightly regulated manner to ensure that the correct proteins are produced accurately at the right time and, in some cases, also in the proper location. With novel techniques such as ribosome profiling and cryogenic electron microscopy, our understanding of this basic biological process is better than ever and continues to grow. Concurrently, increasing attention is focused on how translational regulation in the brain may be disrupted during the progression of various neurological disorders. In fact, translational dysregulation is now recognized as the de facto pathogenic cause for some disorders. Novel mechanisms including ribosome stalling, ribosome-associated quality control, and liquid-liquid phase separation are closely linked to translational regulation, and may thus be involved in the pathogenic process. The relationships between translational dysregulation and neurological disorders, as well as the ways through which we may be able to reverse those detrimental effects, will be examined in this review.

scholarly journals Molecular chaperones and their denaturing effect on client proteins

2020 ◽  
Author(s):  
Sebastian Hiller
Keyword(s):  
Molecular Chaperone ◽  
Molecular Chaperones ◽  
Backbone Dynamics ◽  
Future Research ◽  
Chaperone Function ◽  
Structure And Dynamics ◽  
Client Proteins ◽  
Biophysical Techniques ◽  
Nmr Methods ◽  
Insight Into

Abstract Advanced NMR methods combined with biophysical techniques have recently provided unprecedented insight into structure and dynamics of molecular chaperones and their interaction with client proteins. These studies showed that several molecular chaperones are able to dissolve aggregation-prone polypeptides in aqueous solution. Furthermore, chaperone-bound clients often feature fluid-like backbone dynamics and chaperones have a denaturing effect on clients. Interestingly, these effects that chaperones have on client proteins resemble the effects of known chaotropic substances. Following this analogy, chaotropicity could be a fruitful concept to describe, quantify and rationalize molecular chaperone function. In addition, the observations raise the possibility that at least some molecular chaperones might share functional similarities with chaotropes. We discuss these concepts and outline future research in this direction.

scholarly journals Inhibition of Protein Aggregation by Several Antioxidants

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Samra Hasanbašić ◽  
Alma Jahić ◽  
Selma Berbić ◽  
Magda Tušek Žnidarič ◽  
Eva Žerovnik
Keyword(s):  
Vitamin C ◽  
Protein Aggregation ◽  
Amyloid Fibril ◽  
Fibril Formation ◽  
Amyloid Fibril Formation ◽  
Transmission Electron ◽  
Tht Fluorescence ◽  
Shared Property ◽  
High Concentrations ◽  
Kinetics Of

Amyloid fibril formation is a shared property of all proteins; therefore, model proteins can be used to study this process. We measured protein aggregation of the model amyloid-forming protein stefin B in the presence and absence of several antioxidants. Amyloid fibril formation by stefin B was routinely induced at pH 5 and 10% TFE, at room temperature. The effects of antioxidants NAC, vitamin C, vitamin E, and the three polyphenols resveratrol, quercetin, and curcumin on the kinetics of fibril formation were followed using ThT fluorescence. Concomitantly, the morphology and amount of the aggregates and fibrils were checked by transmission electron microscopy (TEM). The concentration of the antioxidants was varied, and it was observed that different modes of action apply at low or high concentrations relative to the binding constant. In order to obtain more insight into the possible mode of binding, docking of NAC, vitamin C, and all three polyphenols was done to the monomeric form of stefin B.

scholarly journals ROS-induced ROS release in vascular biology: redox-redox signaling

2011 ◽  
Vol 301 (3) ◽  
pp. H647-H653 ◽  
Author(s):  
Natalya S. Zinkevich ◽  
David D. Gutterman
Keyword(s):  
Reactive Oxygen Species ◽  
Adaptive Response ◽  
Vascular Function ◽  
Common Mechanism ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Signaling Function ◽  
A Cell ◽  
Lines Of Evidence

The involvement of reactive oxygen species (ROS) in regulating vascular function both in normal vessels and as part of an adaptive response during disease has been intensively studied. From the recognition that ROS serve as important signaling molecules has emerged multiple lines of evidence that there is a functional connectivity between intracellular sites of ROS production. This cross talk has been termed ROS-induced ROS release (RIRR) and is supported by a variety of observations showing that RIRR is a common mechanism for ROS amplification and regional ROS generation. The compartmentalization of ROS production within a cell is critical to its signaling function and is facilitated by microlocalization of specific scavengers. This review will provide descriptions and examples of important mechanisms of RIRR.

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