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Recent Advances in Protein Misfolding and Aggregation in Neurodegenerative Disorders
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Recent Advances in Protein Misfolding and Aggregation in Neurodegenerative Disorders

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 (30 June 2023) | Viewed by 6474

Special Issue Editor

Dr. Ludmilla A. Morozova-Roche

E-Mail Website
Guest Editor
Department of Medical Biochemistry and Biophsyics, Umeå Univeristy, SE 90187 Umeå, Sweden
Interests: biodiagnostics; amyloid; protein misfolding; neuroinflammation; cellular toxicity; neurodegenerative diseases; blood serum; CSF; bioimaging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Protein damage is increasingly recognised as an important contributor to ageing and to age-associated diseases. Protein misfolding and aggregation are widely implicated in the pathologies of late-onset diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases; amyotrophic lateral sclerosis; and other conditions associated with neurodegeneration. Although neurodegenerative diseases target different neuronal systems, they are mechanistically linked by increased protein disorder and aggregation. Understanding the mechanisms of neurodegenerative diseases in order to define and develop effective treatments is a major challenge in medical research. The amyloid-cascade concept reflects important mechanisms involved in neurodegenerative diseases; however, some of these diseases may be more complex, and other processes such as inflammation can also contribute to pathogeneses. Age-related changes in cellular metabolism affect brain homeostasis and can create conditions permissive of the onset and progression of neurodegenerative disorders. In addition, ordered protein aggregation can fulfil useful functions such as polypeptide storage or sequestration, and can minimise the diffusion of highly reactive and toxic species. Most of the current therapies for amyloid diseases, including Alzheimer’s and Parkinson’s, treat their symptoms, but do not limit their progression. In recent years, extensive studies have been conducted in the field, and knowledge of the underlying mechanisms of amyloid diseases has improved; as a result, new approaches based on the applications of small compounds, auto-immunity, and vaccination have emerged that can halt and reverse amyloid formation, and they have a realistic chance of becoming established therapies within the next decade or so.

We welcome research on a broad range of topics regarding recent advances in our understanding of the molecular and cellular mechanisms governing protein misfolding and amyloid formation (leading to the development of amyloid disease), as well as new research on how these processes can be halted and reversed.

Dr. Ludmilla A. Morozova-Roche
Guest Editor

Manuscript Submission Information

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Keywords

  • amyloid
  • protein misfolding
  • aggregation
  • amyloid disease
  • fibrils
  • oligomers
  • intermediate states
  • self-assembly
  • mechanisms

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Published Papers (3 papers)

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Research

14 pages, 2066 KiB  
Article
The Stabilization of S100A9 Structure by Calcium Inhibits the Formation of Amyloid Fibrils
by Ella Sanders, Rebecca Csondor, Darius Šulskis, Ieva Baronaitė, Vytautas Smirnovas, Luckshi Maheswaran, Jack Horrocks, Rory Munro, Christina Georgiadou, Istvan Horvath, Ludmilla A. Morozova-Roche and Philip T. F. Williamson
Int. J. Mol. Sci. 2023, 24(17), 13200; https://doi.org/10.3390/ijms241713200 - 25 Aug 2023
Cited by 6 | Viewed by 2068
Abstract
The calcium-binding protein S100A9 is recognized as an important component of the brain neuroinflammatory response to the onset and development of neurodegenerative disease. S100A9 is intrinsically amyloidogenic and in vivo co-aggregates with amyloid-β peptide and α-synuclein in Alzheimer’s and Parkinson’s diseases, respectively. It [...] Read more.
The calcium-binding protein S100A9 is recognized as an important component of the brain neuroinflammatory response to the onset and development of neurodegenerative disease. S100A9 is intrinsically amyloidogenic and in vivo co-aggregates with amyloid-β peptide and α-synuclein in Alzheimer’s and Parkinson’s diseases, respectively. It is widely accepted that calcium dyshomeostasis plays an important role in the onset and development of these diseases, and studies have shown that elevated levels of calcium limit the potential for S100A9 to adopt a fibrillar structure. The exact mechanism by which calcium exerts its influence on the aggregation process remains unclear. Here we demonstrate that despite S100A9 exhibiting α-helical secondary structure in the absence of calcium, the protein exhibits significant plasticity with interconversion between different conformational states occurring on the micro- to milli-second timescale. This plasticity allows the population of conformational states that favour the onset of fibril formation. Magic-angle spinning solid-state NMR studies of the resulting S100A9 fibrils reveal that the S100A9 adopts a single structurally well-defined rigid fibrillar core surrounded by a shell of approximately 15–20 mobile residues, a structure that persists even when fibrils are produced in the presence of calcium ions. These studies highlight how the dysregulation of metal ion concentrations can influence the conformational equilibria of this important neuroinflammatory protein to influence the rate and nature of the amyloid deposits formed. Full article
(This article belongs to the Special Issue Recent Advances in Protein Misfolding and Aggregation in Neurodegenerative Disorders)
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11 pages, 1909 KiB  
Communication
Amyloids of α-Synuclein Promote Chemical Transformations of Neuronal Cell Metabolites
by Istvan Horvath, Khadra A. Mohamed, Ranjeet Kumar and Pernilla Wittung-Stafshede
Int. J. Mol. Sci. 2023, 24(16), 12849; https://doi.org/10.3390/ijms241612849 - 16 Aug 2023
Cited by 5 | Viewed by 1524
Abstract
The assembly of α-synuclein into cross-β structured amyloid fibers results in Lewy body deposits and neuronal degeneration in Parkinson’s disease patients. As the cell environment is highly crowded, interactions between the formed amyloid fibers and a range of biomolecules can occur in cells. [...] Read more.
The assembly of α-synuclein into cross-β structured amyloid fibers results in Lewy body deposits and neuronal degeneration in Parkinson’s disease patients. As the cell environment is highly crowded, interactions between the formed amyloid fibers and a range of biomolecules can occur in cells. Although amyloid fibers are considered chemically inert species, recent in vitro work using model substrates has shown α-synuclein amyloids, but not monomers, to catalyze the hydrolysis of ester and phosphoester bonds. To search for putative catalytic activity of α-synuclein amyloids on biologically relevant metabolites, we here incubated α-synuclein amyloids with neuronal SH-SY5Y cell lysates devoid of proteins. LC-MS-based metabolomic (principal component and univariate) analysis unraveled distinct changes in several metabolite levels upon amyloid (but not monomer) incubation. Of 63 metabolites identified, the amounts of four increased (3-hydroxycapric acid, 2-pyrocatechuic acid, adenosine, and NAD), and the amounts of seventeen decreased (including aromatic and apolar amino acids, metabolites in the TCA cycle, keto acids) in the presence of α-synuclein amyloids. Many of these metabolite changes match what has been reported previously in Parkinson’s disease patients and animal–model metabolomics studies. Chemical reactivity of α-synuclein amyloids may be a new gain-of-function that alters the metabolite composition in cells and, thereby, modulates disease progression. Full article
(This article belongs to the Special Issue Recent Advances in Protein Misfolding and Aggregation in Neurodegenerative Disorders)
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12 pages, 2016 KiB  
Article
The Major Components of Cerebrospinal Fluid Dictate the Characteristics of Inhibitors against Amyloid-Beta Aggregation
by Andrius Sakalauskas, Mantas Ziaunys, Ruta Snieckute, Agne Janoniene, Dominykas Veiveris, Mantas Zvirblis, Virginija Dudutiene and Vytautas Smirnovas
Int. J. Mol. Sci. 2023, 24(6), 5991; https://doi.org/10.3390/ijms24065991 - 22 Mar 2023
Cited by 1 | Viewed by 2420
Abstract
The main pathological hallmark of Alzheimer’s disease (AD) is the aggregation of amyloid-β into amyloid fibrils, leading to a neurodegeneration cascade. The current medications are far from sufficient to prevent the onset of the disease, hence requiring more research to find new alternative [...] Read more.
The main pathological hallmark of Alzheimer’s disease (AD) is the aggregation of amyloid-β into amyloid fibrils, leading to a neurodegeneration cascade. The current medications are far from sufficient to prevent the onset of the disease, hence requiring more research to find new alternative drugs for curing AD. In vitro inhibition experiments are one of the primary tools in testing whether a molecule may be potent to impede the aggregation of amyloid-beta peptide (Aβ42). However, kinetic experiments in vitro do not match the mechanism found when aggregating Aβ42 in cerebrospinal fluid. The different aggregation mechanisms and the composition of the reaction mixtures may also impact the characteristics of the inhibitor molecules. For this reason, altering the reaction mixture to resemble components found in cerebrospinal fluid (CSF) is critical to partially compensate for the mismatch between the inhibition experiments in vivo and in vitro. In this study, we used an artificial cerebrospinal fluid that contained the major components found in CSF and performed Aβ42 aggregation inhibition studies using oxidized epigallocatechin-3-gallate (EGCG) and fluorinated benzenesulfonamide VR16-09. This led to a discovery of a complete turnaround of their inhibitory characteristics, rendering EGCG ineffective while significantly improving the efficacy of VR16-09. HSA was the main contributor in the mixture that significantly increased the anti-amyloid characteristics of VR16-09. Full article
(This article belongs to the Special Issue Recent Advances in Protein Misfolding and Aggregation in Neurodegenerative Disorders)
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