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Biomedicines
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Protein Aggregation: Molecular Mechanisms, Determinants and Therapeutic Approaches
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Protein Aggregation: Molecular Mechanisms, Determinants and Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 12240

Special Issue Editor

Dr. Nikolaos N. Louros

E-Mail Website
Guest Editor
VIB - KU Leuven, 3000 Leuven, Belgium
Interests: molecular biophysics; structural biology; structural bioinformatics; cellular biophysics; computational biology; protein structure and stability; protein misfolding; protein aggregation; amyloid formation; functional amyloids; aggregation-prone regions; neurodegenerative disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Macromolecular protein assemblies including protein aggregates, biomolecular condensates, and ordered amyloid fibril formation have been associated with various widespread diseases, spanning from major neurodegenerative disorders to certain forms of cancer. At the same time, amyloid formation has also been shown to support important biological functions starting from humans and extending to single-cell organisms. The recent efflux of structural information on amyloid architecture, combined with studies on the molecular determinants and mechanisms that promote self- and heterotypic assembly, has highlighted certain unresolved properties of protein aggregates, such as structural polymorphism and its differential association to disease, selective vulnerability of specific cell types to certain toxic aggregate species, and complex spreading patterns, while also promoting the design of novel therapeutic approaches against this group of diseases.

MDPI’s Biomedicines is setting up this Special Issue aiming to promote new findings focused on the current understanding of the molecular mechanisms and/or the determinants of macromolecular protein assemblies in both disease and in function, whether that is the formation of functional amyloids or the development of new aggregation-based technologies and strategies for therapeutics and nanomaterials. Our interest extends to studies that uncover new aspects of the cross-interaction interplay of protein assemblies with other biomolecules (e.g., nucleic acids, proteins, lipids) and the role of other factors in this process (pH, salts, post-translational modifications, and more). We aim to highlight recent advances in understanding the structural diversity of protein assemblies spanning from phase-separated biomolecular condensates to oligomers and polymorphic end-state amyloid fibrils and their interplay with proteostatic control mechanisms that regulate their formation and balance in a cellular context.

Dr. Nikolaos N. Louros
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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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
  • functional amyloids
  • macromolecular protein assembly
  • cellular mechanisms of assembly
  • sequence/structure determinants
  • phase separation
  • biomolecular cross-interactions in aggregation
  • role of external factors in aggregation
  • amyloid polymorphism
  • design of functional aggregates
  • aggregation-based technologies and therapeutics

Published Papers (6 papers)

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Research

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21 pages, 6555 KiB  
Article
Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia
by Xiaoyue Zhu, Joseph M. Schrader, Brandon A. Irizarry, Steven O. Smith and William E. Van Nostrand
Biomedicines 2022, 10(11), 2982; https://doi.org/10.3390/biomedicines10112982 - 19 Nov 2022
Cited by 2 | Viewed by 2046
Abstract
Fibrillar amyloid β-protein (Aβ) deposits in the brain, which are primarily composed of Aβ40 or Aβ42 peptides, are key pathological features of Alzheimer’s disease (AD) and related disorders. Although the underlying mechanisms are still not clear, the Aβ fibrils can trigger a number [...] Read more.
Fibrillar amyloid β-protein (Aβ) deposits in the brain, which are primarily composed of Aβ40 or Aβ42 peptides, are key pathological features of Alzheimer’s disease (AD) and related disorders. Although the underlying mechanisms are still not clear, the Aβ fibrils can trigger a number of cellular responses, including activation of astrocytes and microglia. In addition, fibril structures of the Aβ40 and Aβ42 peptides are known to be polymorphic, which poses a challenge for attributing the contribution of different Aβ sequences and structures to brain pathology. Here, we systematically treated primary astrocytes and microglia with single, well-characterized polymorphs of Aβ40 or Aβ42 fibrils, and performed bulk RNA sequencing to assess cell-specific changes in gene expression. A greater number of genes were up-regulated by Aβ42 fibril-treated glial cells (251 and 2133 genes in astrocyte and microglia, respectively) compared with the Aβ40 fibril-treated glial cells (191 and 251 genes in astrocytes and microglia, respectively). Immunolabeling studies in an AD rat model with parenchymal fibrillar Aβ42 plaques confirmed the expression of PAI-1, MMP9, MMP12, CCL2, and C1r in plaque-associated microglia, and iNOS, GBP2, and C3D in plaque-associated astrocytes, validating markers from the RNA sequence data. In order to better understand these Aβ fibril-induced gene changes, we analyzed gene expression patterns using the Ingenuity pathway analysis program. These analyses further highlighted that Aβ42 fibril treatment up-regulated cellular activation pathways and immune response pathways in glial cells, including IL1β and TNFα in astrocytes, and microglial activation and TGFβ1 in microglia. Further analysis revealed that a number of disease-associated microglial (DAM) genes were surprisingly suppressed in Aβ40 fibril treated microglia. Together, the present findings indicate that Aβ42 fibrils generally show similar, but stronger, stimulating activity of glial cells compared with Aβ40 fibril treatment. Full article
(This article belongs to the Special Issue Protein Aggregation: Molecular Mechanisms, Determinants and Therapeutic Approaches)
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16 pages, 5969 KiB  
Article
Atomic Force Microscopy Study of the Temperature and Storage Duration Dependencies of Horseradish Peroxidase Oligomeric State
by Irina A. Ivanova, Maria O. Ershova, Ivan D. Shumov, Anastasia A. Valueva, Yuri D. Ivanov and Tatyana O. Pleshakova
Biomedicines 2022, 10(10), 2645; https://doi.org/10.3390/biomedicines10102645 - 20 Oct 2022
Cited by 2 | Viewed by 1240
Abstract
This paper presents an investigation of the temperature dependence of the oligomeric state of the horseradish peroxidase (HRP) enzyme on the temperature of its solution, and on the solution storage time, at the single-molecule level. Atomic force microscopy has been employed to determine [...] Read more.
This paper presents an investigation of the temperature dependence of the oligomeric state of the horseradish peroxidase (HRP) enzyme on the temperature of its solution, and on the solution storage time, at the single-molecule level. Atomic force microscopy has been employed to determine how the temperature and the storage time of the HRP solution influence its aggregation upon direct adsorption of the enzyme from the solution onto bare mica substrates. In parallel, spectrophotometric measurements have been performed in order to estimate whether the HRP enzymatic activity changes over time upon the storage of the enzyme solution. The temperature dependence of the HRP oligomeric state has been studied within a broad (15–40 °C) temperature range. It has been demonstrated that the storage of the HRP solution for 14 days does not have any considerable effect on the oligomeric state of the enzyme, neither does it affect its activity. At longer storage times, AFM has allowed us to reveal a tendency of HRP to oligomerization during the storage of its buffered solution, while the enzymatic activity remains virtually unchanged even after a 1-month-long storage. By AFM, it has been revealed that after the incubation of a mica substrate in the HRP solution at various temperatures, the content of the mica-adsorbed oligomers increases insignificantly owing to a high-temperature stability of the enzyme. Full article
(This article belongs to the Special Issue Protein Aggregation: Molecular Mechanisms, Determinants and Therapeutic Approaches)
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18 pages, 3552 KiB  
Article
FYCO1 Increase and Effect of Arimoclomol–Treatment in Human VCP–Pathology
by Anne-Katrin Guettsches, Nancy Meyer, René P. Zahedi, Teresinha Evangelista, Thomas Muentefering, Tobias Ruck, Emmanuelle Lacene, Christoph Heute, Humberto Gonczarowska-Jorge, Benedikt Schoser, Sabine Krause, Andreas Hentschel, Matthias Vorgerd and Andreas Roos
Biomedicines 2022, 10(10), 2443; https://doi.org/10.3390/biomedicines10102443 - 30 Sep 2022
Cited by 3 | Viewed by 1482
Abstract
Dominant VCP–mutations cause a variety of neurological manifestations including inclusion body myopathy with early–onset Paget disease and frontotemporal dementia 1 (IBMPFD). VCP encodes a ubiquitously expressed multifunctional protein that is a member of the AAA+ protein family, implicated in multiple cellular functions [...] Read more.
Dominant VCP–mutations cause a variety of neurological manifestations including inclusion body myopathy with early–onset Paget disease and frontotemporal dementia 1 (IBMPFD). VCP encodes a ubiquitously expressed multifunctional protein that is a member of the AAA+ protein family, implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin–dependent protein degradation. The latter function accords with the presence of protein aggregates in muscle biopsy specimens derived from VCP–patients. Studying the proteomic signature of VCP–mutant fibroblasts, we identified a (pathophysiological) increase of FYCO1, a protein involved in autophagosome transport. We confirmed this finding applying immunostaining also in muscle biopsies derived from VCP–patients. Treatment of fibroblasts with arimoclomol, an orphan drug thought to restore physiologic cellular protein repair pathways, ameliorated cellular cytotoxicity in VCP–patient derived cells. This finding was accompanied by increased abundance of proteins involved in immune response with a direct impact on protein clearaqnce as well as by elevation of pro–survival proteins as unravelled by untargeted proteomic profiling. Hence, the combined results of our study reveal a dysregulation of FYCO1 in the context of VCP–etiopathology, highlight arimoclomol as a potential drug and introduce proteins targeted by the pre–clinical testing of this drug in fibroblasts. Full article
(This article belongs to the Special Issue Protein Aggregation: Molecular Mechanisms, Determinants and Therapeutic Approaches)
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17 pages, 3438 KiB  
Article
Rational Generation of Monoclonal Antibodies Selective for Pathogenic Forms of Alpha-Synuclein
by Ebrima Gibbs, Beibei Zhao, Andrei Roman, Steven S. Plotkin, Xubiao Peng, Shawn C. C. Hsueh, Adekunle Aina, Jing Wang, Clay Shyu, Calvin K. Yip, Sung-Eun Nam, Johanne M. Kaplan and Neil R. Cashman
Biomedicines 2022, 10(9), 2168; https://doi.org/10.3390/biomedicines10092168 - 02 Sep 2022
Cited by 3 | Viewed by 2346
Abstract
Misfolded toxic forms of alpha-synuclein (α-Syn) have been implicated in the pathogenesis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). The α-Syn oligomers and soluble fibrils have been shown to mediate neurotoxicity and cell-to-cell propagation [...] Read more.
Misfolded toxic forms of alpha-synuclein (α-Syn) have been implicated in the pathogenesis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). The α-Syn oligomers and soluble fibrils have been shown to mediate neurotoxicity and cell-to-cell propagation of pathology. To generate antibodies capable of selectively targeting pathogenic forms of α-Syn, computational modeling was used to predict conformational epitopes likely to become exposed on oligomers and small soluble fibrils, but not on monomers or fully formed insoluble fibrils. Cyclic peptide scaffolds reproducing these conformational epitopes exhibited neurotoxicity and seeding activity, indicating their biological relevance. Immunization with the conformational epitopes gave rise to monoclonal antibodies (mAbs) with the desired binding profile showing selectivity for toxic α-Syn oligomers and soluble fibrils, with little or no reactivity with monomers, physiologic tetramers, or Lewy bodies. Recognition of naturally occurring soluble α-Syn aggregates in brain extracts from DLB and MSA patients was confirmed by surface plasmon resonance (SPR). In addition, the mAbs inhibited the seeding activity of sonicated pre-formed fibrils (PFFs) in a thioflavin-T fluorescence-based aggregation assay. In neuronal cultures, the mAbs protected primary rat neurons from toxic α-Syn oligomers, reduced the uptake of PFFs, and inhibited the induction of pathogenic phosphorylated aggregates of endogenous α-Syn. Protective antibodies selective for pathogenic species of α-Syn, as opposed to pan α-Syn reactivity, are expected to provide enhanced safety and therapeutic potency by preserving normal α-Syn function and minimizing the diversion of active antibody from the target by the more abundant non-toxic forms of α-Syn in the circulation and central nervous system. Full article
(This article belongs to the Special Issue Protein Aggregation: Molecular Mechanisms, Determinants and Therapeutic Approaches)
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Review

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32 pages, 5394 KiB  
Review
Amyloid Disassembly: What Can We Learn from Chaperones?
by Zaida L. Almeida and Rui M. M. Brito
Biomedicines 2022, 10(12), 3276; https://doi.org/10.3390/biomedicines10123276 - 17 Dec 2022
Cited by 5 | Viewed by 2281
Abstract
Protein aggregation and subsequent accumulation of insoluble amyloid fibrils with cross-β structure is an intrinsic characteristic of amyloid diseases, i.e., amyloidoses. Amyloid formation involves a series of on-pathway and off-pathway protein aggregation events, leading to mature insoluble fibrils that eventually accumulate in multiple [...] Read more.
Protein aggregation and subsequent accumulation of insoluble amyloid fibrils with cross-β structure is an intrinsic characteristic of amyloid diseases, i.e., amyloidoses. Amyloid formation involves a series of on-pathway and off-pathway protein aggregation events, leading to mature insoluble fibrils that eventually accumulate in multiple tissues. In this cascade of events, soluble oligomeric species are formed, which are among the most cytotoxic molecular entities along the amyloid cascade. The direct or indirect action of these amyloid soluble oligomers and amyloid protofibrils and fibrils in several tissues and organs lead to cell death in some cases and organ disfunction in general. There are dozens of different proteins and peptides causing multiple amyloid pathologies, chief among them Alzheimer’s, Parkinson’s, Huntington’s, and several other neurodegenerative diseases. Amyloid fibril disassembly is among the disease-modifying therapeutic strategies being pursued to overcome amyloid pathologies. The clearance of preformed amyloids and consequently the arresting of the progression of organ deterioration may increase patient survival and quality of life. In this review, we compiled from the literature many examples of chemical and biochemical agents able to disaggregate preformed amyloids, which have been classified as molecular chaperones, chemical chaperones, and pharmacological chaperones. We focused on their mode of action, chemical structure, interactions with the fibrillar structures, morphology and toxicity of the disaggregation products, and the potential use of disaggregation agents as a treatment option in amyloidosis. Full article
(This article belongs to the Special Issue Protein Aggregation: Molecular Mechanisms, Determinants and Therapeutic Approaches)
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21 pages, 3470 KiB  
Review
Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates
by Nicolas Papadopoulos, Nuria Suelves, Florian Perrin, Devkee M. Vadukul, Céline Vrancx, Stefan N. Constantinescu and Pascal Kienlen-Campard
Biomedicines 2022, 10(11), 2753; https://doi.org/10.3390/biomedicines10112753 - 29 Oct 2022
Cited by 7 | Viewed by 1983
Abstract
Most neurodegenerative diseases have the characteristics of protein folding disorders, i.e., they cause lesions to appear in vulnerable regions of the nervous system, corresponding to protein aggregates that progressively spread through the neuronal network as the symptoms progress. Alzheimer’s disease is one of [...] Read more.
Most neurodegenerative diseases have the characteristics of protein folding disorders, i.e., they cause lesions to appear in vulnerable regions of the nervous system, corresponding to protein aggregates that progressively spread through the neuronal network as the symptoms progress. Alzheimer’s disease is one of these diseases. It is characterized by two types of lesions: neurofibrillary tangles (NFTs) composed of tau proteins and senile plaques, formed essentially of amyloid peptides (Aβ). A combination of factors ranging from genetic mutations to age-related changes in the cellular context converge in this disease to accelerate Aβ deposition. Over the last two decades, numerous studies have attempted to elucidate how structural determinants of its precursor (APP) modify Aβ production, and to understand the processes leading to the formation of different Aβ aggregates, e.g., fibrils and oligomers. The synthesis proposed in this review indicates that the same motifs can control APP function and Aβ production essentially by regulating membrane protein dimerization, and subsequently Aβ aggregation processes. The distinct properties of these motifs and the cellular context regulate the APP conformation to trigger the transition to the amyloid pathology. This concept is critical to better decipher the patterns switching APP protein conformation from physiological to pathological and improve our understanding of the mechanisms underpinning the formation of amyloid fibrils that devastate neuronal functions. Full article
(This article belongs to the Special Issue Protein Aggregation: Molecular Mechanisms, Determinants and Therapeutic Approaches)
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