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Protein Aggregates Toxicity: New Insights into the Mechanisms
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Protein Aggregates Toxicity: New Insights into the Mechanisms

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

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 23124

Special Issue Editors

Dr. Roberta Cascella

E-Mail Website
Guest Editor
Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, 50134 Florence, Italy
Interests: Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; aberrant protein oligomers (β amyloid peptide, α-synuclein, TDP-43); structure/toxicity relationship; molecular chaperones; glutathione thioesters; oxidative stress; Ca2+ dyshomeostasis; aminosterols; conformational antibodies
Special Issues, Collections and Topics in MDPI journals
Dr. Cristina Cecchi

E-Mail Website
Co-Guest Editor
Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, 50134 Florence, Italy
Interests: Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; aberrant protein oligomers (β amyloid peptide, α-synuclein, TDP-43); structure/toxicity relationship; oxidative stress; glutathione thioesters; Ca2+ dyshomeostasis; molecular chaperones; aminosterols; membrane lipid components (cholesterol and GM1)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A broad range of evidence suggests that the aggregation of misfolded peptides or proteins is the predominant process underlying neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), synucleopathies, prion diseases, and other dementias.  These peptides/proteins convert from their soluble states into aggregated species accumulating within organs and tissues, either as intracellular inclusions or extracellular deposits, causing an imbalance of the intracellular redox status and ion levels, membrane perturbation, mitochondria injury and cell death. To date, the exact molecular pathogenesis of neurodegeneration remains unclear. The progress in the development of neuroprotective therapies has been hindered, because it is difficult to define the right targets for treatment and what should be considered as an efficient neuroprotective agent (or medicament). Thus, understanding the mechanisms of neuronal toxicity should provide insights into new therapeutic strategies for prevention and/or treatment of neurodegenerative diseases.  In this special issue, we invite researchers to contribute original research articles describing novel molecular mechanisms of the toxicity caused by misfolded proteins involved in neurodegenerative disorders. Review articles describing the current state of the art are also welcome.

Prof. Roberta Cascella
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 misfolding
  • Protein aggregation
  • Cellular dyshomeostasis
  • Neuronal membrane
  • Amyloid cytotoxicity

Related Special Issue

Published Papers (5 papers)

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Research

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25 pages, 6100 KiB  
Article
Modeling Parkinson’s Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers
by Laura Boi, Augusta Pisanu, Maria Francesca Palmas, Giuliana Fusco, Ezio Carboni, Maria Antonietta Casu, Valentina Satta, Maria Scherma, Elzbieta Janda, Ignazia Mocci, Giovanna Mulas, Anna Ena, Saturnino Spiga, Paola Fadda, Alfonso De Simone and Anna R. Carta
Int. J. Mol. Sci. 2020, 21(22), 8535; https://doi.org/10.3390/ijms21228535 - 12 Nov 2020
Cited by 19 | Viewed by 2595
Abstract
The accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors [...] Read more.
The accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors for αSynOs-mediated toxicity, involving the interaction with either neurons or glial cells. We previously characterized a human αSynO (H-αSynO) with specific structural properties promoting toxicity against neuronal membranes. Here, we tested the neurotoxic potential of these H-αSynOs in vivo, in relation to the neuropathological and symptomatic features of PD. The H-αSynOs were unilaterally infused into the rat substantia nigra pars compacta (SNpc). Phosphorylated αSyn (p129-αSyn), reactive microglia, and cytokine levels were measured at progressive time points. Additionally, a phagocytosis assay in vitro was performed after microglia pre-exposure to αsynOs. Dopaminergic loss, motor, and cognitive performances were assessed. H-αSynOs triggered p129-αSyn deposition in SNpc neurons and microglia and spread to the striatum. Early and persistent neuroinflammatory responses were induced in the SNpc. In vitro, H-αSynOs inhibited the phagocytic function of microglia. H-αsynOs-infused rats displayed early mitochondrial loss and abnormalities in SNpc neurons, followed by a gradual nigrostriatal dopaminergic loss, associated with motor and cognitive impairment. The intracerebral inoculation of structurally characterized H-αSynOs provides a model of progressive PD neuropathology in rats, which will be helpful for testing neuroprotective therapies. Full article
(This article belongs to the Special Issue Protein Aggregates Toxicity: New Insights into the Mechanisms)
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18 pages, 2657 KiB  
Article
Rationally Designed Antibodies as Research Tools to Study the Structure–Toxicity Relationship of Amyloid-β Oligomers
by Ryan Limbocker, Benedetta Mannini, Rodrigo Cataldi, Shianne Chhangur, Aidan K. Wright, Ryan P. Kreiser, J. Alex Albright, Sean Chia, Johnny Habchi, Pietro Sormanni, Janet R. Kumita, Francesco S. Ruggeri, Christopher M. Dobson, Fabrizio Chiti, Francesco A. Aprile and Michele Vendruscolo
Int. J. Mol. Sci. 2020, 21(12), 4542; https://doi.org/10.3390/ijms21124542 - 25 Jun 2020
Cited by 12 | Viewed by 4557
Abstract
Alzheimer’s disease is associated with the aggregation of the amyloid-β peptide (Aβ), resulting in the deposition of amyloid plaques in brain tissue. Recent scrutiny of the mechanisms by which Aβ aggregates induce neuronal dysfunction has highlighted the importance of the Aβ oligomers of [...] Read more.
Alzheimer’s disease is associated with the aggregation of the amyloid-β peptide (Aβ), resulting in the deposition of amyloid plaques in brain tissue. Recent scrutiny of the mechanisms by which Aβ aggregates induce neuronal dysfunction has highlighted the importance of the Aβ oligomers of this protein fragment. Because of the transient and heterogeneous nature of these oligomers, however, it has been challenging to investigate the detailed mechanisms by which these species exert cytotoxicity. To address this problem, we demonstrate here the use of rationally designed single-domain antibodies (DesAbs) to characterize the structure–toxicity relationship of Aβ oligomers. For this purpose, we use Zn2+-stabilized oligomers of the 40-residue form of Aβ (Aβ40) as models of brain Aβ oligomers and two single-domain antibodies (DesAb18-24 and DesAb34-40), designed to bind to epitopes at residues 18–24 and 34–40 of Aβ40, respectively. We found that the DesAbs induce a change in structure of the Zn2+-stabilized Aβ40 oligomers, generating a simultaneous increase in their size and solvent-exposed hydrophobicity. We then observed that these increments in both the size and hydrophobicity of the oligomers neutralize each other in terms of their effects on cytotoxicity, as predicted by a recently proposed general structure–toxicity relationship, and observed experimentally. These results illustrate the use of the DesAbs as research tools to investigate the biophysical and cytotoxicity properties of Aβ oligomers. Full article
(This article belongs to the Special Issue Protein Aggregates Toxicity: New Insights into the Mechanisms)
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Review

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20 pages, 1258 KiB  
Review
Calcium Dyshomeostasis in Alzheimer’s Disease Pathogenesis
by Roberta Cascella and Cristina Cecchi
Int. J. Mol. Sci. 2021, 22(9), 4914; https://doi.org/10.3390/ijms22094914 - 06 May 2021
Cited by 70 | Viewed by 5648
Abstract
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that is characterized by amyloid β-protein deposition in senile plaques, neurofibrillary tangles consisting of abnormally phosphorylated tau protein, and neuronal loss leading to cognitive decline and dementia. Despite extensive research, the exact mechanisms [...] Read more.
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that is characterized by amyloid β-protein deposition in senile plaques, neurofibrillary tangles consisting of abnormally phosphorylated tau protein, and neuronal loss leading to cognitive decline and dementia. Despite extensive research, the exact mechanisms underlying AD remain unknown and effective treatment is not available. Many hypotheses have been proposed to explain AD pathophysiology; however, there is general consensus that the abnormal aggregation of the amyloid β peptide (Aβ) is the initial event triggering a pathogenic cascade of degenerating events in cholinergic neurons. The dysregulation of calcium homeostasis has been studied considerably to clarify the mechanisms of neurodegeneration induced by Aβ. Intracellular calcium acts as a second messenger and plays a key role in the regulation of neuronal functions, such as neural growth and differentiation, action potential, and synaptic plasticity. The calcium hypothesis of AD posits that activation of the amyloidogenic pathway affects neuronal Ca2+ homeostasis and the mechanisms responsible for learning and memory. Aβ can disrupt Ca2+ signaling through several mechanisms, by increasing the influx of Ca2+ from the extracellular space and by activating its release from intracellular stores. Here, we review the different molecular mechanisms and receptors involved in calcium dysregulation in AD and possible therapeutic strategies for improving the treatment. Full article
(This article belongs to the Special Issue Protein Aggregates Toxicity: New Insights into the Mechanisms)
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33 pages, 2352 KiB  
Review
Therapeutic Strategies to Reduce the Toxicity of Misfolded Protein Oligomers
by Ryan P. Kreiser, Aidan K. Wright, Natalie R. Block, Jared E. Hollows, Lam T. Nguyen, Kathleen LeForte, Benedetta Mannini, Michele Vendruscolo and Ryan Limbocker
Int. J. Mol. Sci. 2020, 21(22), 8651; https://doi.org/10.3390/ijms21228651 - 17 Nov 2020
Cited by 23 | Viewed by 4975
Abstract
The aberrant aggregation of proteins is implicated in the onset and pathogenesis of a wide range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. Mounting evidence indicates that misfolded protein oligomers produced as intermediates in the aggregation process are potent neurotoxic agents in [...] Read more.
The aberrant aggregation of proteins is implicated in the onset and pathogenesis of a wide range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. Mounting evidence indicates that misfolded protein oligomers produced as intermediates in the aggregation process are potent neurotoxic agents in these diseases. Because of the transient and heterogeneous nature of these elusive aggregates, however, it has proven challenging to develop therapeutics that can effectively target them. Here, we review approaches aimed at reducing oligomer toxicity, including (1) modulating the oligomer populations (e.g., by altering the kinetics of aggregation by inhibiting, enhancing, or redirecting the process), (2) modulating the oligomer properties (e.g., through the size–hydrophobicity–toxicity relationship), (3) modulating the oligomer interactions (e.g., by protecting cell membranes by displacing oligomers), and (4) reducing oligomer toxicity by potentiating the protein homeostasis system. We analyze examples of these complementary approaches, which may lead to the development of compounds capable of preventing or treating neurodegenerative disorders associated with protein aggregation. Full article
(This article belongs to the Special Issue Protein Aggregates Toxicity: New Insights into the Mechanisms)
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27 pages, 2704 KiB  
Review
Multiplicity of α-Synuclein Aggregated Species and Their Possible Roles in Disease
by Pablo Gracia, José D. Camino, Laura Volpicelli-Daley and Nunilo Cremades
Int. J. Mol. Sci. 2020, 21(21), 8043; https://doi.org/10.3390/ijms21218043 - 28 Oct 2020
Cited by 34 | Viewed by 4637
Abstract
α-Synuclein amyloid aggregation is a defining molecular feature of Parkinson’s disease, Lewy body dementia, and multiple system atrophy, but can also be found in other neurodegenerative disorders such as Alzheimer’s disease. The process of α-synuclein aggregation can be initiated through alternative nucleation mechanisms [...] Read more.
α-Synuclein amyloid aggregation is a defining molecular feature of Parkinson’s disease, Lewy body dementia, and multiple system atrophy, but can also be found in other neurodegenerative disorders such as Alzheimer’s disease. The process of α-synuclein aggregation can be initiated through alternative nucleation mechanisms and dominated by different secondary processes giving rise to multiple amyloid polymorphs and intermediate species. Some aggregated species have more inherent abilities to induce cellular stress and toxicity, while others seem to be more potent in propagating neurodegeneration. The preference for particular types of polymorphs depends on the solution conditions and the cellular microenvironment that the protein encounters, which is likely related to the distinct cellular locations of α-synuclein inclusions in different synucleinopathies, and the existence of disease-specific amyloid polymorphs. In this review, we discuss our current understanding on the nature and structure of the various types of α-synuclein aggregated species and their possible roles in pathology. Precisely defining these distinct α-synuclein species will contribute to understanding the molecular origins of these disorders, developing accurate diagnoses, and designing effective therapeutic interventions for these highly debilitating neurodegenerative diseases. Full article
(This article belongs to the Special Issue Protein Aggregates Toxicity: New Insights into the Mechanisms)
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