scholarly journals Amyloid Fragmentation and Disaggregation in Yeast and Animals

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1884
Author(s):  
Vitaly V. Kushnirov ◽  
Alexander A. Dergalev ◽  
Alexander I. Alexandrov
Keyword(s):  
Protein Aggregates ◽  
Amyloid Aggregates ◽  
Prion Propagation ◽  
Prion Conversion ◽  
Amyloid Diseases ◽  
Potential Use

Amyloids are filamentous protein aggregates that are associated with a number of incurable diseases, termed amyloidoses. Amyloids can also manifest as infectious or heritable particles, known as prions. While just one prion is known in humans and animals, more than ten prion amyloids have been discovered in fungi. The propagation of fungal prion amyloids requires the chaperone Hsp104, though in excess it can eliminate some prions. Even though Hsp104 acts to disassemble prion fibrils, at normal levels it fragments them into multiple smaller pieces, which ensures prion propagation and accelerates prion conversion. Animals lack Hsp104, but disaggregation is performed by the same complement of chaperones that assist Hsp104 in yeast—Hsp40, Hsp70, and Hsp110. Exogenous Hsp104 can efficiently cooperate with these chaperones in animals and promotes disaggregation, especially of large amyloid aggregates, which indicates its potential as a treatment for amyloid diseases. However, despite the significant effects, Hsp104 and its potentiated variants may be insufficient to fully dissolve amyloid. In this review, we consider chaperone mechanisms acting to disassemble heritable protein aggregates in yeast and animals, and their potential use in the therapy of human amyloid diseases.

Insights into amyloid disease from fly models

2014 ◽  
Vol 56 ◽  
pp. 69-83 ◽  
Author(s):  
Ko-Fan Chen ◽  
Damian C. Crowther
Keyword(s):  
Drosophila Melanogaster ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Disease Pathogenesis ◽  
Amyloid Aggregates ◽  
Aβ Amyloid ◽  
Polypeptide Chains ◽  
Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

scholarly journals Amyloids: The History of Toxicity and Functionality

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 394
Author(s):  
Elmira I. Yakupova ◽  
Liya G. Bobyleva ◽  
Sergey A. Shumeyko ◽  
Ivan M. Vikhlyantsev ◽  
Alexander G. Bobylev
Keyword(s):  
Molecular Structure ◽  
Polypeptide Chain ◽  
Amyloid Plaques ◽  
Protein Aggregates ◽  
Specific Function ◽  
Main Hypothesis ◽  
Amyloid Toxicity ◽  
Amyloid Aggregates ◽  
Aβ Amyloid ◽  
History Of

Proteins can perform their specific function due to their molecular structure. Partial or complete unfolding of the polypeptide chain may lead to the misfolding and aggregation of proteins in turn, resulting in the formation of different structures such as amyloid aggregates. Amyloids are rigid protein aggregates with the cross-β structure, resistant to most solvents and proteases. Because of their resistance to proteolysis, amyloid aggregates formed in the organism accumulate in tissues, promoting the development of various diseases called amyloidosis, for instance Alzheimer’s diseases (AD). According to the main hypothesis, it is considered that the cause of AD is the formation and accumulation of amyloid plaques of Aβ. That is why Aβ-amyloid is the most studied representative of amyloids. Therefore, in this review, special attention is paid to the history of Aβ-amyloid toxicity. We note the main problems with anti-amyloid therapy and write about new views on amyloids that can play positive roles in the different organisms including humans.

scholarly journals Disaggregases, molecular chaperones that resolubilize protein aggregates

2015 ◽  
Vol 87 (2 suppl) ◽  
pp. 1273-1292 ◽  
Author(s):  
David Z. Mokry ◽  
Josielle Abrahão ◽  
Carlos H.I. Ramos
Keyword(s):  
Heat Shock ◽  
Molecular Chaperones ◽  
Protein Function ◽  
Protein Aggregates ◽  
Cell Physiology ◽  
Biological Processes ◽  
Loss Of Function ◽  
Prion Propagation ◽  
Shock Proteins

The process of folding is a seminal event in the life of a protein, as it is essential for proper protein function and therefore cell physiology. Inappropriate folding, or misfolding, can not only lead to loss of function, but also to the formation of protein aggregates, an insoluble association of polypeptides that harm cell physiology, either by themselves or in the process of formation. Several biological processes have evolved to prevent and eliminate the existence of non-functional and amyloidogenic aggregates, as they are associated with several human pathologies. Molecular chaperones and heat shock proteins are specialized in controlling the quality of the proteins in the cell, specifically by aiding proper folding, and dissolution and clearance of already formed protein aggregates. The latter is a function of disaggregases, mainly represented by the ClpB/Hsp104 subfamily of molecular chaperones, that are ubiquitous in all organisms but, surprisingly, have no orthologs in the cytosol of metazoan cells. This review aims to describe the characteristics of disaggregases and to discuss the function of yeast Hsp104, a disaggregase that is also involved in prion propagation and inheritance.

scholarly journals Role of Hsp104 in the Propagation and Inheritance of the [Het-s] Prion

2007 ◽  
Vol 18 (12) ◽  
pp. 4803-4812 ◽  
Author(s):  
Laurent Malato ◽  
Suzana Dos Reis ◽  
Laura Benkemoun ◽  
Raimon Sabaté ◽  
Sven J. Saupe
Keyword(s):  
Meiotic Drive ◽  
Protein Aggregates ◽  
Propagation Rate ◽  
Podospora Anserina ◽  
Wild Type ◽  
Prion Propagation ◽  
Meiotic Instability

The chaperones of the ClpB/HSP100 family play a central role in thermotolerance in bacteria, plants, and fungi by ensuring solubilization of heat-induced protein aggregates. In addition in yeast, Hsp104 was found to be required for prion propagation. Herein, we analyze the role of Podospora anserina Hsp104 (PaHsp104) in the formation and propagation of the [Het-s] prion. We show that ΔPaHsp104 strains propagate [Het-s], making [Het-s] the first native fungal prion to be propagated in the absence of Hsp104. Nevertheless, we found that [Het-s]-propagon numbers, propagation rate, and spontaneous emergence are reduced in a ΔPaHsp104 background. In addition, inactivation of PaHsp104 leads to severe meiotic instability of [Het-s] and abolishes its meiotic drive activity. Finally, we show that ΔPaHSP104 strains are less susceptible than wild type to infection by exogenous recombinant HET-s(218–289) prion amyloids. Like [URE3] and [PIN+] in yeast but unlike [PSI+], [Het-s] is not cured by constitutive PaHsp104 overexpression. The observed effects of PaHsp104 inactivation are consistent with the described role of Hsp104 in prion aggregate shearing in yeast. However, Hsp104-dependency appears less stringent in P. anserina than in yeast; presumably because in Podospora prion propagation occurs in a syncitium.

scholarly journals The uptake of tau amyloid fibrils is facilitated by the cellular prion protein and hampers prion propagation in cultured cells

2020 ◽  
Author(s):  
Elena De Cecco ◽  
Luigi Celauro ◽  
Silvia Vanni ◽  
Micaela Grandolfo ◽  
Adriano Aguzzi ◽  
...  
Keyword(s):  
Prion Protein ◽  
Amyloid Fibrils ◽  
Cultured Cells ◽  
Neuroblastoma Cells ◽  
Cellular Prion Protein ◽  
Brain Diseases ◽  
Gene Encoding ◽  
Prion Propagation ◽  
Prion Conversion ◽  
Tau Fibrils

AbstractTauopathies are prevalent, invariably fatal brain diseases for which no cure is available. Tauopathies progressively affect the brain through cell-to-cell transfer of tau protein amyloids, yet the spreading mechanisms are unknown. Here we show that the cellular prion protein (PrPC) facilitates the uptake of tau aggregates by cultured cells, possibly by acting as an endocytic receptor. In mouse neuroblastoma cells, we found that tau amyloids bind to PrPC; internalization of tau fibrils was reduced in isogenic cells devoid of the gene encoding PrPC. Antibodies against N-proximal epitopes of PrPC impaired the binding of tau amyloids and decreased their uptake. Surprisingly, exposure of chronically prion-infected cells to tau amyloids reduced the accumulation of aggregated prion protein; this effect lasted for more than 72 hours after amyloid removal. These results point to bidirectional interactions between the two proteins: whilst PrPC mediates the entrance of tau fibrils in cells, PrPSc buildup is greatly reduced in their presence, possibly because of an impairment in the prion conversion process.

scholarly journals Lysozyme Fibrils Alter the Mechanism of Insulin Amyloid Aggregation

2021 ◽  
Vol 22 (4) ◽  
pp. 1775
Author(s):  
Mantas Ziaunys ◽  
Andrius Sakalauskas ◽  
Tomas Sneideris ◽  
Vytautas Smirnovas
Keyword(s):  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Protein Aggregates ◽  
Amyloid Aggregation ◽  
Amyloid Aggregates ◽  
Affected Tissue ◽  
New Ideas

Protein aggregation into amyloid fibrils is linked to multiple disorders. The understanding of how natively non-harmful proteins convert to these highly cytotoxic amyloid aggregates is still not sufficient, with new ideas and hypotheses being presented each year. Recently it has been shown that more than one type of protein aggregates may co-exist in the affected tissue of patients suffering from amyloid-related disorders, sparking the idea that amyloid aggregates formed by one protein may induce another protein’s fibrillization. In this work, we examine the effect that lysozyme fibrils have on insulin amyloid aggregation. We show that not only do lysozyme fibrils affect insulin nucleation, but they also alter the mechanism of its aggregation.

scholarly journals TheGinkgo bilobaExtract EGb 761 Modulates Proteasome Activity and Polyglutamine Protein Aggregation

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Marcel Stark ◽  
Christian Behl
Keyword(s):  
Protein Degradation ◽  
Cultured Cells ◽  
Protein Aggregates ◽  
Proteasome Activity ◽  
Protein Homeostasis ◽  
Cellular Model ◽  
Egb 761 ◽  
Polyq Protein ◽  
Polyglutamine Protein ◽  
Potential Use

The standardizedGinkgo bilobaextract EGb 761 has well-described antioxidative activities and effects on different cytoprotective signaling pathways. Consequently, a potential use of EGb 761 in neurodegenerative diseases has been proposed. A common characteristic feature of a variety of such disorders is the pathologic formation of protein aggregates, suggesting a crucial role for protein homeostasis. In this study, we show that EGb 761 increased the catalytic activity of the proteasome and enhanced protein degradation in cultured cells. We further investigated this effect in a cellular model of Huntington’s disease (HD) by employing cells expressing pathologic variants of a polyglutamine protein (polyQ protein). We show that EGb 761 affected these cells by (i) increasing proteasome activity and (ii) inducing a more efficient degradation of aggregation-prone proteins. These results demonstrate a novel activity of EGb 761 on protein aggregates by enhancing proteasomal protein degradation, suggesting a therapeutic use in neurodegenerative disorders with a disturbed protein homeostasis.

scholarly journals Magnetic Nanoparticles Applications for Amyloidosis Study and Detection: A Review

Nanomaterials ◽  
2018 ◽  
Vol 8 (9) ◽  
pp. 740 ◽  
Author(s):  
Jonathan Pansieri ◽  
Matthieu Gerstenmayer ◽  
François Lux ◽  
Sebastien Mériaux ◽  
Olivier Tillement ◽  
...  
Keyword(s):  
Magnetic Nanoparticles ◽  
Clinical Applications ◽  
Antibody Fragments ◽  
Pittsburgh Compound B ◽  
Amyloidogenic Proteins ◽  
Model Of Alzheimer’S Disease ◽  
Amyloid Aggregates ◽  
Amyloid Diseases ◽  
The Brain

Magnetic nanoparticles (MNPs) have great potential in biomedical and clinical applications because of their many unique properties. This contribution provides an overview of the MNPs mainly used in the field of amyloid diseases. The first part discusses their use in understanding the amyloid mechanisms of fibrillation, with emphasis on their ability to control aggregation of amyloidogenic proteins. The second part deals with the functionalization by various moieties of numerous MNPs’ surfaces (molecules, peptides, antibody fragments, or whole antibodies of MNPs) for the detection and the quantification of amyloid aggregates. The last part of this review focuses on the use of MNPs for magnetic-resonance-based amyloid imaging in biomedical fields, with particular attention to the application of gadolinium-based paramagnetic nanoparticles (AGuIX), which have been recently developed. Biocompatible AGuIX nanoparticles show favorable characteristics for in vivo use, such as nanometric and straightforward functionalization. Their properties have enabled their application in MRI. Here, we report that AGuIX nanoparticles grafted with the Pittsburgh compound B can actively target amyloid aggregates in the brain, beyond the blood–brain barrier, and remain the first step in observing amyloid plaques in a mouse model of Alzheimer’s disease.

scholarly journals Prion propagation can occur in a prokaryote and requires the ClpB chaperone

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Andy H Yuan ◽  
Sean J Garrity ◽  
Entela Nako ◽  
Ann Hochschild
Keyword(s):  
Escherichia Coli ◽  
Prion Protein ◽  
De Novo ◽  
Protein Aggregates ◽  
Transmissible Spongiform Encephalopathies ◽  
Yeast Prion ◽  
Spongiform Encephalopathies ◽  
E Coli ◽  
Prion Propagation ◽  
Bacterial Domain

Prions are self-propagating protein aggregates that are characteristically transmissible. In mammals, the PrP protein can form a prion that causes the fatal transmissible spongiform encephalopathies. Prions have also been uncovered in fungi, where they act as heritable, protein-based genetic elements. We previously showed that the yeast prion protein Sup35 can access the prion conformation in Escherichia coli. Here, we demonstrate that E. coli can propagate the Sup35 prion under conditions that do not permit its de novo formation. Furthermore, we show that propagation requires the disaggregase activity of the ClpB chaperone. Prion propagation in yeast requires Hsp104 (a ClpB ortholog), and prior studies have come to conflicting conclusions about ClpB's ability to participate in this process. Our demonstration of ClpB-dependent prion propagation in E. coli suggests that the cytoplasmic milieu in general and a molecular machine in particular are poised to support protein-based heredity in the bacterial domain of life.

scholarly journals Quantitative assessment of chaperone binding to amyloid aggregates identifies specificity of Hsp40 interaction with yeast prion fibrils

2020 ◽  
Vol 20 (4) ◽  
Author(s):  
Yury A Barbitoff ◽  
Andrew G Matveenko ◽  
Stanislav A Bondarev ◽  
Evgeniia M Maksiutenko ◽  
Alexandra V Kulikova ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Protein Quality ◽  
Tight Binding ◽  
Yeast Prion ◽  
Dimerization Domain ◽  
Yeast Prions ◽  
Amyloid Aggregates ◽  
Independent Mechanism ◽  
Prion Propagation ◽  
Chaperone Binding

ABSTRACT Yeast self-perpetuating protein aggregates (yeast prions) provide a framework to investigate the interaction of misfolded proteins with the protein quality control machinery. The major component of this system that facilitates propagation of all known yeast amyloid prions is the Hsp104 chaperone that catalyzes fibril fragmentation. Overproduction of Hsp104 cures some yeast prions via a fragmentation-independent mechanism. Importantly, major cytosolic chaperones of the Hsp40 group, Sis1 and Ydj1, oppositely affect yeast prion propagation, and are capable of stimulating different activities of Hsp104. In this work, we developed a quantitative method to investigate the Hsp40 binding to amyloid aggregates. We demonstrate that Sis1 binds fibrils formed by the Sup35NM protein with higher affinity compared to Ydj1. Moreover, the interaction of Sis1 with the fibrils formed by the other yeast prion protein, Rnq1, is orders of magnitude weaker. We show that the deletion of the dimerization domain of Sis1 (crucial for the curing of [PSI+] by excess Hsp104) decreases its affinity to both Sup35NM and Rnq1 fibrils. Taken together, these results suggest that tight binding of Hsp40 to the amyloid fibrils is likely to enhance aggregate malpartition instead of fibril fragmentation.

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