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Pathological and Functional Amyloid Fibrils 2.0
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Pathological and Functional Amyloid Fibrils 2.0

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

Deadline for manuscript submissions: closed (15 August 2023) | Viewed by 12197

Special Issue Editors

Prof. Dr. Konstantin K. Turoverov

E-Mail Website
Guest Editor
Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Ave., 194064 St. Petersburg, Russia
Interests: protein structure, conformation and dynamics; globule and intrinsically disordered proteins; macromolecular crowding; membraneless organelles; protein aggregates; amyloid fibrils formation and structure; biosensors; biomarkers on the basis of fluorescent proteins and phytochromes; photophysics of fluorescent dyes; molecular rotors; intrinsic fluorescence of proteins; spectrofluorimetry device development
Special Issues, Collections and Topics in MDPI journals
Dr. Irina M. Kuznetsova

E-Mail Website
Guest Editor
Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Ave., 194064 St. Petersburg, Russia
Interests: amyloid fibrils; thioflafin T fluorescence; equilibrium microdialysis; globule and intrinsically disordered proteins; proteins aggregattion; macromolecular crowding; membraneless organelles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Amyloid fibrils were first discovered in the tissue of patients suffering from neurodegenerative diseases. This led to a keen interest in the study of their structure, causes and mechanisms of occurrence, toxicity, etc. It was soon established that amyloid fibrils are regular, β-sheet-enriched, long, nanoscale aggregates of proteins with β-strands running perpendicular to the long axis of the fibril. However, a more in-depth study of amyloid fibrils showed that amyloid fibrils formed by various amyloidogenic proteins differ significantly in structure, rate of formation, prone to aggregation, toxicity, etc. It turned out that not all amyloid fibrils are harmful. Many amyloid fibrils are non-toxic and have important functions. The formation of amyloid fibrils can disrupt various technological processes, and at the same time, the unique strength properties of amyloid fibrils are increasingly used in the development of new technologies.

The aim of this Special Issue entitled " Pathological and Functional Amyloid Fibrils 2.0" is to collect, under one umbrella, the most important modern ideas about mechanisms of formation, structure, stability, prone to plaque formation and other important fitures of a wide range of amyloid fibrils. Perhaps this will shed light on the fundamental differences and similarities of pathological and non-pathological amyloid fibrils. Experimental papers, up-to-date review articles, and commentaries are all welcomed. In addition, the Special Issue will provide a forum to exchange views and discuss the prospects for studying amyloid fibrils in the next few years.

Prof. Dr. Konstantin K. Turoverov
Dr. Irina M. Kuznetsova
Guest Editors

Manuscript Submission Information

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Keywords

  • amyloid fibrils formation and structure
  • intrinsically disordered proteins
  • protein aggregates
  • amyloid fibrils and membrane-less organelles
  • amyloid fibrils disease, harmful amyloid fibrils
  • functional amyloid fibrils
  • methods of amyloid fibrils investigation

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Published Papers (5 papers)

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12 pages, 3882 KiB  
Article
Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease Pathology
by Topaz Kreiser, Ilana Sogolovsky-Bard, Dor Zaguri, Shira Shaham-Niv, Dana Laor Bar-Yosef and Ehud Gazit
Int. J. Mol. Sci. 2023, 24(21), 15999; https://doi.org/10.3390/ijms242115999 - 6 Nov 2023
Cited by 2 | Viewed by 1587
Abstract
Inborn error of metabolism disorders (IEMs) are a family of diseases resulting from single-gene mutations that lead to the accumulation of metabolites that are usually toxic or interfere with normal cell function. The etiological link between metabolic alteration and the symptoms of IEMs [...] Read more.
Inborn error of metabolism disorders (IEMs) are a family of diseases resulting from single-gene mutations that lead to the accumulation of metabolites that are usually toxic or interfere with normal cell function. The etiological link between metabolic alteration and the symptoms of IEMs is still elusive. Several metabolites, which accumulate in IEMs, were shown to self-assemble to form ordered structures. These structures display the same biophysical, biochemical, and biological characteristics as proteinaceous amyloid fibrils. Here, we have demonstrated, for the first time, the ability of each of the branched-chain amino acids (BCAAs) that accumulate in maple syrup urine disease (MSUD) to self-assemble into amyloid-like fibrils depicted by characteristic morphology, binding to indicative amyloid-specific dyes and dose-dependent cytotoxicity by a late apoptosis mechanism. We could also detect the presence of the assemblies in living cells. In addition, by employing several in vitro techniques, we demonstrated the ability of known polyphenols to inhibit the formation of the BCAA fibrils. Our study implies that BCAAs possess a pathological role in MSUD, extends the paradigm-shifting concept regarding the toxicity of metabolite amyloid-like structures, and suggests new pathological targets that may lead to highly needed novel therapeutic opportunities for this orphan disease. Full article
(This article belongs to the Special Issue Pathological and Functional Amyloid Fibrils 2.0)
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21 pages, 4898 KiB  
Article
Amyloid Fibrils of Pisum sativum L. Vicilin Inhibit Pathological Aggregation of Mammalian Proteins
by Maksim I. Sulatsky, Mikhail V. Belousov, Anastasiia O. Kosolapova, Ekaterina V. Mikhailova, Maria N. Romanenko, Kirill S. Antonets, Irina M. Kuznetsova, Konstantin K. Turoverov, Anton A. Nizhnikov and Anna I. Sulatskaya
Int. J. Mol. Sci. 2023, 24(16), 12932; https://doi.org/10.3390/ijms241612932 - 18 Aug 2023
Cited by 2 | Viewed by 1461
Abstract
Although incurable pathologies associated with the formation of highly ordered fibrillar protein aggregates called amyloids have been known for about two centuries, functional roles of amyloids have been studied for only two decades. Recently, we identified functional amyloids in plants. These amyloids formed [...] Read more.
Although incurable pathologies associated with the formation of highly ordered fibrillar protein aggregates called amyloids have been known for about two centuries, functional roles of amyloids have been studied for only two decades. Recently, we identified functional amyloids in plants. These amyloids formed using garden pea Pisum sativum L. storage globulin and vicilin, accumulated during the seed maturation and resisted treatment with gastric enzymes and canning. Thus, vicilin amyloids ingested with food could interact with mammalian proteins. In this work, we analyzed the effects of vicilin amyloids on the fibril formation of proteins that form pathological amyloids. We found that vicilin amyloids inhibit the fibrillogenesis of these proteins. In particular, vicilin amyloids decrease the number and length of lysozyme amyloid fibrils; the length and width of β-2-microglobulin fibrils; the number, length and the degree of clustering of β-amyloid fibrils; and, finally, they change the structure and decrease the length of insulin fibrils. Such drastic influences of vicilin amyloids on the pathological amyloids’ formation cause the alteration of their toxicity for mammalian cells, which decreases for all tested amyloids with the exception of insulin. Taken together, our study, for the first time, demonstrates the anti-amyloid effect of vicilin fibrils and suggests the mechanisms underlying this phenomenon. Full article
(This article belongs to the Special Issue Pathological and Functional Amyloid Fibrils 2.0)
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13 pages, 4750 KiB  
Article
Aβ40 Aggregation under Changeable Conditions
by Jofre Seira Curto, Maria Rosario Fernandez, Josep Cladera, Núria Benseny-Cases and Natalia Sanchez de Groot
Int. J. Mol. Sci. 2023, 24(9), 8408; https://doi.org/10.3390/ijms24098408 - 7 May 2023
Viewed by 2260
Abstract
Homeostasis is crucial for cell function, and disturbances in homeostasis can lead to health disorders. Under normal conditions, intracellular pH is maintained between 7.35 and 7.45. Altered endosomal and lysosomal pH together with a general drop in brain pH are associated with the [...] Read more.
Homeostasis is crucial for cell function, and disturbances in homeostasis can lead to health disorders. Under normal conditions, intracellular pH is maintained between 7.35 and 7.45. Altered endosomal and lysosomal pH together with a general drop in brain pH are associated with the aggregation of amyloid-β-peptide (Aβ) and the development of Alzheimer’s disease. Under acidic conditions, close to the Aβ isoelectric point, the absence of charges favors the formation of intermolecular contacts and promotes aggregation. Here, we analyzed how pH levels affect the aggregation of Aβ40 considering the variations in brain pH and the coexistence of different aggregated conformations. Our results suggest that different macromolecular conformations can interact with each other and influence the aggregation process. In addition, we showed that neutral pH and physiological salt concentrations favor a slow aggregation, resulting in ordered, stable fibrils, with low cytotoxic effects. Overall, we highlight the complexity of the aggregation processes occurring in different physiological and pathological environments. Full article
(This article belongs to the Special Issue Pathological and Functional Amyloid Fibrils 2.0)
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14 pages, 3073 KiB  
Article
Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation
by Laura De Luca, Serena Vittorio, Samuel Peña-Díaz, Giovanna Pitasi, Marc Fornt-Suñé, Federica Bucolo, Salvador Ventura and Rosaria Gitto
Int. J. Mol. Sci. 2022, 23(23), 14844; https://doi.org/10.3390/ijms232314844 - 27 Nov 2022
Cited by 6 | Viewed by 2845
Abstract
α-Synuclein (α-Syn) aggregates are implicated in Parkinson’s disease (PD), so inhibitors of α-Syn aggregation have been intensively explored. It has been demonstrated that small molecules might be able to reduce α-Syn aggregation in fibrils, thus exerting neuroprotective effects in models of PD. To [...] Read more.
α-Synuclein (α-Syn) aggregates are implicated in Parkinson’s disease (PD), so inhibitors of α-Syn aggregation have been intensively explored. It has been demonstrated that small molecules might be able to reduce α-Syn aggregation in fibrils, thus exerting neuroprotective effects in models of PD. To expand our knowledge about the structural requirements for blocking the recognition process into the oligomeric assembly of α-Syn aggregates, we performed a ligand-based virtual screening procedure using two well-known α-Syn aggregation inhibitors, SynuClean-D and ZPD-2, as query compounds. A collection of thirty-four compounds bearing distinct chemical functionalities and mutual chemical features were studied in a Th-T fluorescence test, thus identifying 5-(2,6-dinitro-4-(trifluoromethyl)benzyl)-1-methyl-1H-tetrazole (named MeSC-04) as a potent α-Syn amyloid formation inhibitor that demonstrated similar behavior when compared to SynuClean-D in the thioflavin-T-monitored kinetic assays, with both molecules reducing the number and size of amyloid fibrils, as evidenced by electron microscopy. Molecular modeling studies suggested the binding mode of MeSC-04 through the identification of putative druggable pockets on α-syn fibrils and a subsequent consensus docking methodology. Overall, this work could furnish new insights in the development of α-Syn amyloid inhibitors from synthetic sources. Full article
(This article belongs to the Special Issue Pathological and Functional Amyloid Fibrils 2.0)
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26 pages, 4199 KiB  
Article
New Evidence on a Distinction between Aβ40 and Aβ42 Amyloids: Thioflavin T Binding Modes, Clustering Tendency, Degradation Resistance, and Cross-Seeding
by Anna I. Sulatskaya, Georgy N. Rychkov, Maksim I. Sulatsky, Ekaterina V. Mikhailova, Nadezhda M. Melnikova, Veronika S. Andozhskaya, Irina M. Kuznetsova and Konstantin K. Turoverov
Int. J. Mol. Sci. 2022, 23(10), 5513; https://doi.org/10.3390/ijms23105513 - 15 May 2022
Cited by 11 | Viewed by 3336
Abstract
The relative abundance of two main Abeta-peptide types with different lengths, Aβ40 and Aβ42, determines the severity of the Alzheimer’s disease progression. However, the factors responsible for different behavior patterns of these peptides in the amyloidogenesis process remain unknown. In this comprehensive study, [...] Read more.
The relative abundance of two main Abeta-peptide types with different lengths, Aβ40 and Aβ42, determines the severity of the Alzheimer’s disease progression. However, the factors responsible for different behavior patterns of these peptides in the amyloidogenesis process remain unknown. In this comprehensive study, new evidence on Aβ40 and Aβ42 amyloid polymorphism was obtained using a wide range of experimental approaches, including custom-designed approaches. We have for the first time determined the number of modes of thioflavin T (ThT) binding to Aβ40 and Aβ42 fibrils and their binding parameters using a specially developed approach based on the use of equilibrium microdialysis, which makes it possible to distinguish between the concentration of the injected dye and the concentration of dye bound to fibrils. The binding sites of one of these modes located at the junction of adjacent fibrillar filaments were predicted by molecular modeling techniques. We assumed that the sites of the additional mode of ThT-Aβ42 amyloid binding observed experimentally (which are not found in the case of Aβ40 fibrils) are localized in amyloid clots, and the number of these sites could be used for estimation of the level of fiber clustering. We have shown the high tendency of Aβ42 fibers to form large clots compared to Aβ40 fibrils. It is probable that this largely determines the high resistance of Aβ42 amyloids to destabilizing effects (denaturants, ionic detergents, ultrasonication) and their explicit cytotoxic effect, which we have shown. Remarkably, cross-seeding of Aβ40 fibrillogenesis using the preformed Aβ42 fibrils changes the morphology and increases the stability and cytotoxicity of Aβ40 fibrils. The differences in the tendency to cluster and resistance to external factors of Aβ40 and Aβ42 fibrils revealed here may be related to the distinct role they play in the deposition of amyloids and, therefore, differences in pathogenicity in Alzheimer’s disease. Full article
(This article belongs to the Special Issue Pathological and Functional Amyloid Fibrils 2.0)
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