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Protein Folding, Misfolding, and Related Diseases
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Protein Folding, Misfolding, and Related Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 April 2026) | Viewed by 10756

Special Issue Editor

Prof. Dr. Ludmilla Morozova-Roche

E-Mail Website
Guest Editor
Department of Medical Biochemistry and Biophysics, Umea University, 90781 Umea, Sweden
Interests: biophysics; amyloid formation; amyloid cytotoxicity; protein misfolding; amyloid-neuroinflammatory cascade; amyloid diagnostics and prognostics; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In order to function properly, proteins fold into their native three-dimensional conformations. Protein folding is governed by physico-chemical properties of the amino acids constituting its polypeptide chain, and leads to the minimization of polypeptide chain free energy. Multiple chaperone systems are required to fold proteins correctly in a cellular environment. In addition, degradation pathways participate by destroying improperly folded proteins. However, the intricacy of this multisystem processes provides many opportunities for an error. As a result, many diseases are fundamentally rooted in the protein folding or misfolding problem that all cells need to resolve in order to maintain their function and integrity.

Among those, amyloid formation emerged as a characteristic of a growing group of protein misfolding diseases associated with the formation of insoluble polypeptide depositions. Amyloids are most commonly accumulated extracellularly, as in the cases of Alzheimer’s disease and systemic amyloidoses, but they can also grow intracellularly, as in Parkinson’s and Huntington’s diseases. In order to assemble into amyloid fibrils, proteins often need to undergo dramatic structural conversion.

In this Special Issue, you are welcome to address the issues concerning the underlying molecular and cellular mechanisms of protein folding and alternative structural conversion into misfolded species, how these processes may lead to disease or are mitigated by protective cellular mechanisms. The prospective treatments of protein misfolding diseases will be also highlighted.

Prof. Dr. Ludmilla Morozova-Roche
Guest Editor

Manuscript Submission Information

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Keywords

  • protein folding
  • misfolding
  • amyloid
  • neurodegenerative diseases
  • chaperons
  • mechanisms
  • regulation

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Published Papers (4 papers)

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Research

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19 pages, 1699 KB  
Article
Monoclonal Gammopathy of Neurological Significance: Toward an Integrated Hematologic–Neurologic Perspective—A Single-Center Retrospective Study
by Sorina Badelita, Larisa Zidaru, Sinziana Barbu, Iulia Ursuleac, Mirela Draghici, Camelia Dobrea, Monica Popescu and Daniel Coriu
Int. J. Mol. Sci. 2026, 27(9), 3847; https://doi.org/10.3390/ijms27093847 - 26 Apr 2026
Viewed by 258
Abstract
Monoclonal gammopathies of clinical significance (MGCSs) are entities in which a small hematological clone produces a monoclonal immunoglobulin capable of causing organ damage. Neurological involvement remains difficult to diagnose and treat, especially in the context of incidental monoclonal gammopathy of undetermined significance (MGUS)–peripheral [...] Read more.
Monoclonal gammopathies of clinical significance (MGCSs) are entities in which a small hematological clone produces a monoclonal immunoglobulin capable of causing organ damage. Neurological involvement remains difficult to diagnose and treat, especially in the context of incidental monoclonal gammopathy of undetermined significance (MGUS)–peripheral neuropathy (PN) associations. We conducted a single-center retrospective study at Fundeni Clinical Institute, Bucharest, from January 2015 to December 2025. The reference population included 300 patients with MGUS. The diagnosis of MGNS was established clinically and/or electrophysiologically, with the exclusion of alternative causes of neuropathy. In total, 35 patients with MGNS were identified (prevalence 11.7%). Neuropathy was more common in IgM MGUS (36.7%) compared to IgG (15%), IgA (14.3%), or light chain MGUS (16.7%), with an increased risk for IgM (OR 3.27, p < 0.001). A total of 88.5% of patients received hematological treatment; neurological response was noted in the majority of treated patients. Mortality was 14.3%, and median OS was not reached. Our findings confirm the dissociation between low clonal load and the severity of organ involvement. IgM MGUS is associated with a significantly increased risk of neuropathy, supporting the need for systematic screening for MGUS in patients with PN and for a multidisciplinary approach. Full article
(This article belongs to the Special Issue Protein Folding, Misfolding, and Related Diseases)
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15 pages, 1315 KB  
Article
New Role of Protein Misfolding Corrector in the ER Stress-Inflammation Axis: Possible Therapeutic Indication in Neuronal and Epithelial Tumor Cells
by Michela Pecoraro, Adele Serra, Maria Julia Lamberti, Maria Pascale and Silvia Franceschelli
Int. J. Mol. Sci. 2025, 26(22), 10846; https://doi.org/10.3390/ijms262210846 - 8 Nov 2025
Cited by 1 | Viewed by 1174
Abstract
Protein misfolding diseases are characterized by structurally abnormal proteins that lose their functionality, resulting in cellular and tissue dysfunction. Neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, share a common etiopathogenesis characterize by the accumulation of misfolded proteins. These proteins autonomously [...] Read more.
Protein misfolding diseases are characterized by structurally abnormal proteins that lose their functionality, resulting in cellular and tissue dysfunction. Neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, share a common etiopathogenesis characterize by the accumulation of misfolded proteins. These proteins autonomously aggregate within neuronal cells, triggering inflammation and cell death. The accumulation of misfolded proteins triggers endoplasmic reticulum (ER) stress, leading to alter Ca2+ homeostasis. This prolonged stress condition induces the cleavage of procaspase 4 which is resident in ER and activates NF-kB pathway activation, leading to inflammatory responses and cell death. In this study, the efficacy of the drug Vx-445 (Elexacaftor), used in the pharmacological treatment of cystic fibrosis, was assessed in human adenocarcinomic basal alveolar epithelial (A549) and neuronal (SH-SY5Y) cell lines, where ER stress was induced by Thapsigargin. The aim was to assess whether the corrector was able to reduce ER stress by restoring cellular homeostasis and, probably, the proper folding of misfolded proteins and reducing the inflammatory response triggered by these events. Therefore, protein levels of IkBα, p-STAT 3 and COXII were analyzed by flow cytofluorimetry, while Ca2+ content was measured by spectrofluorimetry. The results obtained suggest a significant effect of Vx-445 in restoring cellular homeostasis, leading to reduced expression of inflammation-related proteins, such as IL-6, tested by ELISA. Although preliminary, these results encourage further studies to explore the potential repurpose of Vx-445 as a therapeutic candidate for conditions involving ER stress and chronic inflammatory diseases associated with protein misfolding, beyond its current use in cystic fibrosis. Full article
(This article belongs to the Special Issue Protein Folding, Misfolding, and Related Diseases)
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Review

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27 pages, 3006 KB  
Review
Pathological and Functional Brain Amyloids: A New Concept Explaining the Differences
by Alexey P. Galkin, Vladimir A. Mitkevich, Alexander A. Makarov, Anna A. Valina and Evgeniy I. Sysoev
Int. J. Mol. Sci. 2025, 26(21), 10459; https://doi.org/10.3390/ijms262110459 - 28 Oct 2025
Viewed by 1825
Abstract
In recent years, amyloid proteins that perform vital functions in the brain have been characterized. The question of why some amyloids are neurotoxic while others are harmless remains open. Here, we provide a brief overview of pathological and functional brain amyloids and present [...] Read more.
In recent years, amyloid proteins that perform vital functions in the brain have been characterized. The question of why some amyloids are neurotoxic while others are harmless remains open. Here, we provide a brief overview of pathological and functional brain amyloids and present a comparative analysis of their amino acid sequences based on the percentage of hydrophobic and charged residues, as well as their enrichment in glutamine, asparagine, serine, and glycine. We demonstrate that pathological and functional brain amyloid proteins, along with their amyloidogenic fragments, do not differ in amino acid composition, contrary to previous assumptions. The ability of an amyloid to cause toxicity can instead be explained by the concept of “available targets”. Evidence from studies of pathological amyloids demonstrate that their toxicity is determined not only by a loss of function but also by aberrant interactions with specific targets, such as PrPC or mitochondrial membranes. Binding to these targets triggers pathological cascades that ultimately lead to cell death. In contrast, such targets are inaccessible to functional amyloids, either because of localized translation and protein sequestration within specialized cellular structures, or because their interactions with physiological partners prevent binding to dangerous targets. Full article
(This article belongs to the Special Issue Protein Folding, Misfolding, and Related Diseases)
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34 pages, 6557 KB  
Review
Beyond Misfolding: A New Paradigm for the Relationship Between Protein Folding and Aggregation
by Seong Il Choi, Yoontae Jin, Yura Choi and Baik L. Seong
Int. J. Mol. Sci. 2025, 26(1), 53; https://doi.org/10.3390/ijms26010053 - 24 Dec 2024
Cited by 6 | Viewed by 6119
Abstract
Aggregation is intricately linked to protein folding, necessitating a precise understanding of their relationship. Traditionally, aggregation has been viewed primarily as a sequential consequence of protein folding and misfolding. However, this conventional paradigm is inherently incomplete and can be deeply misleading. Remarkably, it [...] Read more.
Aggregation is intricately linked to protein folding, necessitating a precise understanding of their relationship. Traditionally, aggregation has been viewed primarily as a sequential consequence of protein folding and misfolding. However, this conventional paradigm is inherently incomplete and can be deeply misleading. Remarkably, it fails to adequately explain how intrinsic and extrinsic factors, such as charges and cellular macromolecules, prevent intermolecular aggregation independently of intramolecular protein folding and structure. The pervasive inconsistencies between protein folding and aggregation call for a new framework. In all combined reactions of molecules, both intramolecular and intermolecular rate (or equilibrium) constants are mutually independent; accordingly, intrinsic and extrinsic factors independently affect both rate constants. This universal principle, when applied to protein folding and aggregation, indicates that they should be treated as two independent yet interconnected processes. Based on this principle, a new framework provides groundbreaking insights into misfolding, Anfinsen’s thermodynamic hypothesis, molecular chaperones, intrinsic chaperone-like activities of cellular macromolecules, intermolecular repulsive force-driven aggregation inhibition, proteome solubility maintenance, and proteinopathies. Consequently, this paradigm shift not only refines our current understanding but also offers a more comprehensive view of how aggregation is coupled to protein folding in the complex cellular milieu. Full article
(This article belongs to the Special Issue Protein Folding, Misfolding, and Related Diseases)
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