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Clearance, Degradation and Transport of Protein Aggregates

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 26371

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Special Issue Editor

Dr. Mehdi Kabani

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Guest Editor

Institut de Biologie François Jacob, Molecular Imaging Research Center (MIRCen), Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Laboratoire des Maladies Neurodégénératives, Centre National de la Recherche Scientifique (CNRS), Paris, Fontenay‐aux‐Roses, F‐92265 France

Special Issue Information

Dear colleagues,

Protein aggregation results from stress, aging, environmental insults, or mutations and is a challenge for all cells and all organisms. It can take many forms, from amorphous aggregates to highly structured amyloid fibrils. Protein misfolding and aggregation are often cytotoxic and can lead to a wide variety of diseases, although functional protein assemblies have been described. Cells use a wide range of defense mechanisms to cope with protein aggregation, such as molecular chaperones, proteolysis by proteasomes or lysosomes, formation of protein inclusions, and export via extracellular vesicles.

For this Special Issue, we welcome original research and mini-review articles covering the mechanistic, physiological, and pathological aspects of protein aggregation. Articles discussing methodological approaches to and issues with the investigation of protein aggregation in test tubes or living cells and organisms are also encouraged.

Dr. Mehdi Kabani
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

protein aggregation
molecular chaperones
amyloids
prions
protein quality control
proteasome
autophagy
extracellular vesicles
disaggregates
protein inclusions.

Published Papers (7 papers)

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Research

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12 pages, 3080 KiB

Open AccessArticle

Extracellular Protein Aggregates Colocalization and Neuronal Dystrophy in Comorbid Alzheimer’s and Creutzfeldt–Jakob Disease: A Micromorphological Pilot Study on 20 Brains

by Nikol Jankovska, Tomas Olejar and Radoslav Matej

Int. J. Mol. Sci. 2021, 22(4), 2099; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042099 - 20 Feb 2021

Cited by 5 | Viewed by 2583

Abstract

Alzheimer’s disease (AD) and sporadic Creutzfeldt–Jakob disease (sCJD) are both characterized by extracellular pathologically conformed aggregates of amyloid proteins—amyloid β-protein (Aβ) and prion protein (PrP^Sc), respectively. To investigate the potential morphological colocalization of Aβ and PrP^Sc aggregates, we examined the hippocampal regions (archicortex and neocortex) of 20 subjects with confirmed comorbid AD and sCJD using neurohistopathological analyses, immunohistochemical methods, and confocal fluorescent microscopy. Our data showed that extracellular Aβ and PrP^Sc aggregates tended to be, in most cases, located separately, and “compound” plaques were relatively rare. We observed PrP^Sc plaque-like structures in the periphery of the non-compact parts of Aβ plaques, as well as in tau protein-positive dystrophic structures. The AD ABC score according to the NIA-Alzheimer’s association guidelines, and prion protein subtype with codon 129 methionine–valine (M/V) polymorphisms in sCJD, while representing key characteristics of these diseases, did not correlate with the morphology of the Aβ/PrP^Sc co-aggregates. However, our data showed that PrP^Sc aggregation could dominate during co-aggregation with non-compact Aβ in the periphery of Aβ plaques. Full article

(This article belongs to the Special Issue Clearance, Degradation and Transport of Protein Aggregates)

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18 pages, 5559 KiB

Open AccessArticle

Myosin Binding Protein-C Forms Amyloid-Like Aggregates In Vitro

by Liya G. Bobyleva, Sergey A. Shumeyko, Elmira I. Yakupova, Alexey K. Surin, Oxana V. Galzitskaya, Hiroshi Kihara, Alexander A. Timchenko, Maria A. Timchenko, Nikita V. Penkov, Alexey D. Nikulin, Mariya Yu. Suvorina, Nikolay V. Molochkov, Mikhail Yu. Lobanov, Roman S. Fadeev, Ivan M. Vikhlyantsev and Alexander G. Bobylev

Int. J. Mol. Sci. 2021, 22(2), 731; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020731 - 13 Jan 2021

Cited by 5 | Viewed by 3015

Abstract

This work investigated in vitro aggregation and amyloid properties of skeletal myosin binding protein-C (sMyBP-C) interacting in vivo with proteins of thick and thin filaments in the sarcomeric A-disc. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) found a rapid (5–10 min) formation of large (>2 μm) aggregates. sMyBP-C oligomers formed both at the initial 5–10 min and after 16 h of aggregation. Small angle X-ray scattering (SAXS) and DLS revealed sMyBP-C oligomers to consist of 7–10 monomers. TEM and atomic force microscopy (AFM) showed sMyBP-C to form amorphous aggregates (and, to a lesser degree, fibrillar structures) exhibiting no toxicity on cell culture. X-ray diffraction of sMyBP-C aggregates registered reflections attributed to a cross-β quaternary structure. Circular dichroism (CD) showed the formation of the amyloid-like structure to occur without changes in the sMyBP-C secondary structure. The obtained results indicating a high in vitro aggregability of sMyBP-C are, apparently, a consequence of structural features of the domain organization of proteins of this family. Formation of pathological amyloid or amyloid-like sMyBP-C aggregates in vivo is little probable due to amino-acid sequence low identity (<26%), alternating ordered/disordered regions in the protein molecule, and S–S bonds providing for general stability. Full article

(This article belongs to the Special Issue Clearance, Degradation and Transport of Protein Aggregates)

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16 pages, 2710 KiB

Open AccessArticle

Fluorescence Lifetime and Intensity of Thioflavin T as Reporters of Different Fibrillation Stages: Insights Obtained from Fluorescence Up-Conversion and Particle Size Distribution Measurements

by Nataliya R. Rovnyagina, Gleb S. Budylin, Yuri G. Vainer, Tatiana N. Tikhonova, Sergey L. Vasin, Alexander A. Yakovlev, Victor O. Kompanets, Sergey V. Chekalin, Alexander V. Priezzhev and Evgeny A. Shirshin

Int. J. Mol. Sci. 2020, 21(17), 6169; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176169 - 26 Aug 2020

Cited by 14 | Viewed by 4316

Abstract

Thioflavin T (ThT) assay is extensively used for studying fibrillation kinetics in vitro. However, the differences in the time course of ThT fluorescence intensity and lifetime and other physical parameters of the system, such as particle size distribution, raise questions about the correct interpretation of the aggregation kinetics. In this work, we focused on the investigation of the mechanisms, which underlay the difference in sensitivity of ThT fluorescence intensity and lifetime to the formation of protein aggregates during fibrillation by the example of insulin and during binding to globular proteins. The assessment of aggregate sizes and heterogeneity was performed using dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). Using the sub-nanosecond resolution measurements, it was shown that the ThT lifetime is sensitive to the appearance of as much as a few percent of ThT bound to the high-affinity sites that occur simultaneously with an abrupt increase of the average particle size, particles concentration, and size heterogeneity. The discrepancy between ThT fluorescence intensity and a lifetime can be explained as the consequence of a ThT molecule fraction with ultrafast decay and weak fluorescence. These ThT molecules can only be detected using time-resolved fluorescence measurements in the sub-picosecond time domain. The presence of a bound ThT subpopulation with similar photophysical properties was also demonstrated for globular proteins that were attributed to non-specifically bound ThT molecules with a non-rigid microenvironment. Full article

(This article belongs to the Special Issue Clearance, Degradation and Transport of Protein Aggregates)

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Review

Jump to: Research

13 pages, 1298 KiB

Open AccessReview

Aggrephagy Deficiency in the Placenta: A New Pathogenesis of Preeclampsia

by Akitoshi Nakashima, Tomoko Shima, Sayaka Tsuda, Aiko Aoki, Mihoko Kawaguchi, Atsushi Furuta, Ippei Yasuda, Satoshi Yoneda, Akemi Yamaki-Ushijima, Shi-Bin Cheng, Surendra Sharma and Shigeru Saito

Int. J. Mol. Sci. 2021, 22(5), 2432; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052432 - 28 Feb 2021

Cited by 14 | Viewed by 6031

Abstract

Aggrephagy is defined as the selective degradation of aggregated proteins by autophagosomes. Protein aggregation in organs and cells has been highlighted as a cause of multiple diseases, including neurodegenerative diseases, cardiac failure, and renal failure. Aggregates could pose a hazard for cell survival. Cells exhibit three main mechanisms against the accumulation of aggregates: protein refolding by upregulation of chaperones, reduction of protein overload by translational inhibition, and protein degradation by the ubiquitin–proteasome and autophagy–lysosome systems. Deletion of autophagy-related genes reportedly contributes to intracellular protein aggregation in vivo. Some proteins recognized in aggregates in preeclamptic placentas include those involved in neurodegenerative diseases. As aggregates are derived both intracellularly and extracellularly, special endocytosis for extracellular aggregates also employs the autophagy machinery. In this review, we discuss how the deficiency of aggrephagy and/or macroautophagy leads to poor placentation, resulting in preeclampsia or fetal growth restriction. Full article

(This article belongs to the Special Issue Clearance, Degradation and Transport of Protein Aggregates)

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15 pages, 1229 KiB

Open AccessReview

The Autophagy Pathway: A Critical Route in the Disposal of Alpha 1-Antitrypsin Aggregates That Holds Many Mysteries

by Celine Leon and Marion Bouchecareilh

Int. J. Mol. Sci. 2021, 22(4), 1875; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041875 - 13 Feb 2021

Cited by 8 | Viewed by 2765

Abstract

The maintenance of proteome homeostasis, or proteostasis, is crucial for preserving cellular functions and for cellular adaptation to environmental challenges and changes in physiological conditions. The capacity of cells to maintain proteostasis requires precise control and coordination of protein synthesis, folding, conformational maintenance, and clearance. Thus, protein degradation by the ubiquitin–proteasome system (UPS) or the autophagy–lysosomal system plays an essential role in cellular functions. However, failure of the UPS or the autophagic process can lead to the development of various diseases (aging-associated diseases, cancer), thus both these pathways have become attractive targets in the treatment of protein conformational diseases, such as alpha 1-antitrypsin deficiency (AATD). The Z alpha 1-antitrypsin (Z-AAT) misfolded variant of the serine protease alpha 1-antitrypsin (AAT) is caused by a structural change that predisposes it to protein aggregation and dramatic accumulation in the form of inclusion bodies within liver hepatocytes. This can lead to clinically significant liver disease requiring liver transplantation in childhood or adulthood. Treatment of mice with autophagy enhancers was found to reduce hepatic Z-AAT aggregate levels and protect them from AATD hepatotoxicity. To date, liver transplantation is the only curative therapeutic option for patients with AATD-mediated liver disease. Therefore, the development and discovery of new therapeutic approaches to delay or overcome disease progression is a top priority. Herein, we review AATD-mediated liver disease and the overall process of autophagy. We highlight the role of this system in the regulation of Z-variant degradation and its implication in AATD-medicated liver disease, including some open questions that remain challenges in the field and require further elucidation. Finally, we discuss how manipulation of autophagy could provide multiple routes of therapeutic benefit in AATD-mediated liver disease. Full article

(This article belongs to the Special Issue Clearance, Degradation and Transport of Protein Aggregates)

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Graphical abstract

13 pages, 2499 KiB

Open AccessReview

Extracellular Vesicles-Encapsulated Yeast Prions and What They Can Tell Us about the Physical Nature of Propagons

by Mehdi Kabani

Int. J. Mol. Sci. 2021, 22(1), 90; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010090 - 23 Dec 2020

Cited by 4 | Viewed by 2747

Abstract

The yeast Saccharomyces cerevisiae hosts an ensemble of protein-based heritable traits, most of which result from the conversion of structurally and functionally diverse cytoplasmic proteins into prion forms. Among these, [PSI⁺], [URE3] and [PIN⁺] are the most well-documented prions and arise from the assembly of Sup35p, Ure2p and Rnq1p, respectively, into insoluble fibrillar assemblies. Yeast prions propagate by molecular chaperone-mediated fragmentation of these aggregates, which generates small self-templating seeds, or propagons. The exact molecular nature of propagons and how they are faithfully transmitted from mother to daughter cells despite spatial protein quality control are not fully understood. In [PSI⁺] cells, Sup35p forms detergent-resistant assemblies detectable on agarose gels under semi-denaturant conditions and cytosolic fluorescent puncta when the protein is fused to green fluorescent protein (GFP); yet, these macroscopic manifestations of [PSI⁺] do not fully correlate with the infectivity measured during growth by the mean of protein infection assays. We also discovered that significant amounts of infectious Sup35p particles are exported via extracellular (EV) and periplasmic (PV) vesicles in a growth phase and glucose-dependent manner. In the present review, I discuss how these vesicles may be a source of actual propagons and a suitable vehicle for their transmission to the bud. Full article

(This article belongs to the Special Issue Clearance, Degradation and Transport of Protein Aggregates)

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19 pages, 9373 KiB

Open AccessReview

Extracellular Amyloid Deposits in Alzheimer’s and Creutzfeldt–Jakob Disease: Similar Behavior of Different Proteins?

by Nikol Jankovska, Tomas Olejar and Radoslav Matej

Int. J. Mol. Sci. 2021, 22(1), 7; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010007 - 22 Dec 2020

Cited by 13 | Viewed by 4208

Abstract

Neurodegenerative diseases are characterized by the deposition of specific protein aggregates, both intracellularly and/or extracellularly, depending on the type of disease. The extracellular occurrence of tridimensional structures formed by amyloidogenic proteins defines Alzheimer’s disease, in which plaques are composed of amyloid β-protein, while in prionoses, the same term “amyloid” refers to the amyloid prion protein. In this review, we focused on providing a detailed didactic description and differentiation of diffuse, neuritic, and burnt-out plaques found in Alzheimer’s disease and kuru-like, florid, multicentric, and neuritic plaques in human transmissible spongiform encephalopathies, followed by a systematic classification of the morphological similarities and differences between the extracellular amyloid deposits in these disorders. Both conditions are accompanied by the extracellular deposits that share certain signs, including neuritic degeneration, suggesting a particular role for amyloid protein toxicity. Full article

(This article belongs to the Special Issue Clearance, Degradation and Transport of Protein Aggregates)

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