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Cellular and Molecular Mechanisms of Neurodegenerative Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (20 January 2022) | Viewed by 37051

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Special Issue Editor

Prof. Adrian Israelson

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Guest Editor

Ben-Gurion University of the Negev, Beer Sheba, Israel
Interests: ALS; neurodegeneration; misfolded proteins; misfolded SOD1; mutant SOD1 models; protein aggregation; MIF; chaperones; mitochondrial dysfunction

Special Issue Information

Dear colleagues,

Neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, ALS, etc.) currently represent a major challenge to public health worldwide, especially as our population continues to age. Neurodegeneration is characterized by the progressive degeneration of specific neuronal populations driven by, as of yet, unknown cellular and molecular pathogenic mechanisms. Since there is no cure or effective treatment for these disorders, the characterization of the specific mechanisms that lead to neurodegeneration, as well as the identification of potential novel targets for the development of new therapeutic strategies, is a major priority in this field.

The aim of this Special Issue is to provide an overview of the main cellular and molecular pathogenic mechanisms, elucidated thus far, that lead to the onset and progression of these devastating neurodegenerative disorders, highlighting both the common and specific pathways involved in each one of them.

Prof. Adrian Israelson
Guest Editor

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Keywords

neurodegeneration
Alzheimer’s disease
Parkinson’s disease
Huntington’s disease
motor neuron disease
amyotrophic lateral sclerosis
ALS
neurodegenerative diseases
ER stress
mitochondrial dysfunction
misfolded proteins
protein aggregation

Published Papers (10 papers)

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Research

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11 pages, 1878 KiB

Open AccessArticle

Amelioration of Experimental Autoimmune Encephalomyelitis in Alzheimer’s Disease Mouse Models: A Potential Role for Aβ

by Changjie Shi, Jiaxue Cha, Junyuan Gong, Shaodeng Wang, Peng Zeng, Junjiang Lian, Bowen Zhang, Qiuhong Hua, Jie Lv, Changsheng Du, Xin Xie and Ru Zhang

Cells 2022, 11(6), 1004; https://doi.org/10.3390/cells11061004 - 16 Mar 2022

Cited by 1 | Viewed by 2766

Abstract

Emerging data have highlighted the coexistence of multiple sclerosis (MS) and Alzheimer’s disease (AD), both of which are common central nervous system degenerative diseases with a heavy burden on patients, their families, and society. However, it is unclear how MS progresses under an AD pathological background. We aimed to address the question of how MS progresses under an AD pathological background. We induced the experimental autoimmune encephalomyelitis (EAE) model of MS in two types of AD mouse models, Tg6799 and APP/PS1 mice. We found that, compared with wild-type mice, the clinical symptoms of EAE were significantly ameliorated in APP/PS1 mice but not in Tg6799 mice. Moreover, a much lower level of serum Aβ was observed in Tg6799 mice. EAE clinical symptoms in Tg6799 and C57BL/6J mice were ameliorated by intraperitoneal injection of Aβ42. Peripheral administration of Aβ42 peptides was able to inhibit Th17 development in vivo, which is likely to occur through the inhibition of IL-6 production in dendritic cells. Our findings revealed that AD and EAE could coexist in the same mouse, and Aβ residing in peripheral circulation likely plays an anti-inflammatory role in preventing EAE progression. These findings reveal the potential benefit of Aβ, one of the supervillains of AD, at least in certain contexts. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)

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16 pages, 3671 KiB

Open AccessArticle

The Modulatory Effects of DMF on Microglia in Aged Mice Are Sex-Specific

by Virginia Mela, Aline Sayd Gaban, Eoin O’Neill, Sibylle Bechet, Aífe Walsh and Marina A. Lynch

Cells 2022, 11(4), 729; https://doi.org/10.3390/cells11040729 - 18 Feb 2022

Cited by 9 | Viewed by 3121

Abstract

There is a striking sex-related difference in the prevalence of many neurodegenerative diseases, highlighting the need to consider whether treatments may exert sex-specific effects. A change in microglial activation state is a common feature of several neurodegenerative diseases and is considered to be a key factor in driving the inflammation that characterizes these conditions. Among the changes that have been described is a switch in microglial metabolism towards glycolysis which is associated with production of inflammatory mediators and reduced function. Marked sex-related differences in microglial number, phenotype and function have been described in late embryonic and early postnatal life in rodents and some reports suggest that sexual dimorphism extends into adulthood and age and, in models of Alzheimer’s disease, the changes are more profound in microglia from female, compared with male, mice. Dimethyl fumarate (DMF) is a fumaric acid ester used in the treatment of psoriasis and relapsing remitting multiple sclerosis and, while its mechanism of action is unclear, it possesses anti-inflammatory and anti-oxidant properties and also impacts on cell metabolism. Here we treated 16–18-month-old female and male mice with DMF for 1 month and assessed its effect on microglia. The evidence indicates that it exerted sex-specific effects on microglial morphology and metabolism, reducing glycolysis only in microglia from female mice. The data suggest that this may result from its ability to inactivate glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)

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20 pages, 3133 KiB

Open AccessArticle

Single-Cell RNA-Seq Analysis of Olfactory Mucosal Cells of Alzheimer’s Disease Patients

by Riikka Lampinen, Mohammad Feroze Fazaludeen, Simone Avesani, Tiit Örd, Elina Penttilä, Juha-Matti Lehtola, Toni Saari, Sanna Hannonen, Liudmila Saveleva, Emma Kaartinen, Francisco Fernández Acosta, Marcela Cruz-Haces, Heikki Löppönen, Alan Mackay-Sim, Minna U. Kaikkonen, Anne M. Koivisto, Tarja Malm, Anthony R. White, Rosalba Giugno, Sweelin Chew and Katja M. Kanninen Show full author list Hide full author list

Cells 2022, 11(4), 676; https://doi.org/10.3390/cells11040676 - 15 Feb 2022

Cited by 18 | Viewed by 6024

Abstract

Olfaction is orchestrated by olfactory mucosal cells located in the upper nasal cavity. Olfactory dysfunction manifests early in several neurodegenerative disorders including Alzheimer’s disease, however, disease-related alterations to the olfactory mucosal cells remain poorly described. The aim of this study was to evaluate the olfactory mucosa differences between cognitively healthy individuals and Alzheimer’s disease patients. We report increased amyloid-beta secretion in Alzheimer’s disease olfactory mucosal cells and detail cell-type-specific gene expression patterns, unveiling 240 differentially expressed disease-associated genes compared to the cognitively healthy controls, and five distinct cell populations. Overall, alterations of RNA and protein metabolism, inflammatory processes, and signal transduction were observed in multiple cell populations, suggesting their role in Alzheimer’s disease-related olfactory mucosa pathophysiology. Furthermore, the single-cell RNA-sequencing proposed alterations in gene expression of mitochondrially located genes in AD OM cells, which were verified by functional assays, demonstrating altered mitochondrial respiration and a reduction of ATP production. Our results reveal disease-related changes of olfactory mucosal cells in Alzheimer’s disease and demonstrate the utility of single-cell RNA sequencing data for investigating molecular and cellular mechanisms associated with the disease. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)

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18 pages, 3987 KiB

Open AccessArticle

RNA Molecular Signature Profiling in PBMCs of Sporadic ALS Patients: HSP70 Overexpression Is Associated with Nuclear SOD1

by Maria Garofalo, Cecilia Pandini, Matteo Bordoni, Emanuela Jacchetti, Luca Diamanti, Stephana Carelli, Manuela Teresa Raimondi, Daisy Sproviero, Valeria Crippa, Serena Carra, Angelo Poletti, Orietta Pansarasa, Stella Gagliardi and Cristina Cereda

Cells 2022, 11(2), 293; https://doi.org/10.3390/cells11020293 - 15 Jan 2022

Cited by 5 | Viewed by 2901

Abstract

Superoxide dismutase 1 (SOD1) is one of the causative genes associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder. SOD1 aggregation contributes to ALS pathogenesis. A fraction of the protein is localized in the nucleus (nSOD1), where it seems to be involved in the regulation of genes participating in the oxidative stress response and DNA repair. Peripheral blood mononuclear cells (PBMCs) were collected from sporadic ALS (sALS) patients (n = 18) and healthy controls (n = 12) to perform RNA-sequencing experiments and differential expression analysis. Patients were stratified into groups with “high” and “low” levels of nSOD1. We obtained different gene expression patterns for high- and low-nSOD1 patients. Differentially expressed genes in high nSOD1 form a cluster similar to controls compared to the low-nSOD1 group. The pathways activated in high-nSOD1 patients are related to the upregulation of HSP70 molecular chaperones. We demonstrated that, in this condition, the DNA damage is reduced, even under oxidative stress conditions. Our findings highlight the importance of the nuclear localization of SOD1 as a protective mechanism in sALS patients. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)

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Graphical abstract

19 pages, 3573 KiB

Open AccessArticle

Transcriptome Analysis of Induced Pluripotent Stem Cells and Neuronal Progenitor Cells, Derived from Discordant Monozygotic Twins with Parkinson’s Disease

by Ivan N. Vlasov, Anelya Kh. Alieva, Ekaterina V. Novosadova, Elena L. Arsenyeva, Anna V. Rosinskaya, Suzanna A. Partevian, Igor A. Grivennikov and Maria I. Shadrina

Cells 2021, 10(12), 3478; https://doi.org/10.3390/cells10123478 - 9 Dec 2021

Cited by 4 | Viewed by 3149

Abstract

Parkinson’s Disease (PD) is a widespread severe neurodegenerative disease that is characterized by pronounced deficiency of the dopaminergic system and disruption of the function of other neuromodulator systems. Although heritable genetic factors contribute significantly to PD pathogenesis, only a small percentage of sporadic cases of PD can be explained using known genetic risk factors. Due to that, it could be inferred that changes in gene expression could be important for explaining a significant percentage of PD cases. One of the ways to investigate such changes, while minimizing the effect of genetic factors on experiment, are the study of PD discordant monozygotic twins. In the course of the analysis of transcriptome data obtained from IPSC and NPCs, 20 and 1906 differentially expressed genes were identified respectively. We have observed an overexpression of TNF in NPC cultures, derived from twin with PD. Through investigation of gene interactions and gene involvement in biological processes, we have arrived to a hypothesis that TNF could play a crucial role in PD-related changes occurring in NPC derived from twins with PD, and identified INHBA, WNT7A and DKK1 as possible downstream effectors of TNF. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)

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Review

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14 pages, 1225 KiB

Open AccessReview

Crosstalk between Biomolecular Condensates and Proteostasis

by Emmanuel Amzallag and Eran Hornstein

Cells 2022, 11(15), 2415; https://doi.org/10.3390/cells11152415 - 4 Aug 2022

Cited by 7 | Viewed by 2582

Abstract

Proper homeostasis of the proteome, referred to as proteostasis, is maintained by chaperone-dependent refolding of misfolded proteins and by protein degradation via the ubiquitin-proteasome system and the autophagic machinery. This review will discuss a crosstalk between biomolecular condensates and proteostasis, whereby the crowding of proteostasis factors into macromolecular assemblies is often established by phase separation of membraneless biomolecular condensates. Specifically, ubiquitin and other posttranslational modifications come into play as agents of phase separation, essential for the formation of condensates and for ubiquitin-proteasome system activity. Furthermore, an intriguing connection associates malfunction of the same pathways to the accumulation of misfolded and ubiquitinated proteins in aberrant condensates, the formation of protein aggregates, and finally, to the pathogenesis of neurodegenerative diseases. The crosstalk between biomolecular condensates and proteostasis is an emerging theme in cellular and disease biology and further studies will focus on delineating specific molecular pathways involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)

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20 pages, 1260 KiB

Open AccessEditor’s ChoiceReview

Implications of Poly(A) Tail Processing in Repeat Expansion Diseases

by Paweł Joachimiak, Adam Ciesiołka, Grzegorz Figura and Agnieszka Fiszer

Cells 2022, 11(4), 677; https://doi.org/10.3390/cells11040677 - 15 Feb 2022

Cited by 4 | Viewed by 3314

Abstract

Repeat expansion diseases are a group of more than 40 disorders that affect mainly the nervous and/or muscular system and include myotonic dystrophies, Huntington’s disease, and fragile X syndrome. The mutation-driven expanded repeat tract occurs in specific genes and is composed of tri- to dodeca-nucleotide-long units. Mutant mRNA is a pathogenic factor or important contributor to the disease and has great potential as a therapeutic target. Although repeat expansion diseases are quite well known, there are limited studies concerning polyadenylation events for implicated transcripts that could have profound effects on transcript stability, localization, and translation efficiency. In this review, we briefly present polyadenylation and alternative polyadenylation (APA) mechanisms and discuss their role in the pathogenesis of selected diseases. We also discuss several methods for poly(A) tail measurement (both transcript-specific and transcriptome-wide analyses) and APA site identification—the further development and use of which may contribute to a better understanding of the correlation between APA events and repeat expansion diseases. Finally, we point out some future perspectives on the research into repeat expansion diseases, as well as APA studies. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)

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46 pages, 1445 KiB

Open AccessFeature PaperReview

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

by Shirel Argueti-Ostrovsky, Leenor Alfahel, Joy Kahn and Adrian Israelson

Cells 2021, 10(9), 2438; https://doi.org/10.3390/cells10092438 - 16 Sep 2021

Cited by 20 | Viewed by 4475

Abstract

Multiple neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are being suggested to have common cellular and molecular pathological mechanisms, characterized mainly by protein misfolding and aggregation. These large inclusions, most likely, represent an end stage of a molecular cascade; however, the soluble misfolded proteins, which take part in earlier steps of this cascade, are the more toxic players. These pathological proteins, which characterize each specific disease, lead to the selective vulnerability of different neurons, likely resulting from a combination of different intracellular mechanisms, including mitochondrial dysfunction, ER stress, proteasome inhibition, excitotoxicity, oxidative damage, defects in nucleocytoplasmic transport, defective axonal transport and neuroinflammation. Damage within these neurons is enhanced by damage from the nonneuronal cells, via inflammatory processes that accelerate the progression of these diseases. In this review, while acknowledging the hallmark proteins which characterize the most common NDDs; we place specific focus on the common overlapping mechanisms leading to disease pathology despite these different molecular players and discuss how this convergence may occur, with the ultimate hope that therapies effective in one disease may successfully translate to another. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)

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16 pages, 3516 KiB

Open AccessReview

Intersection of Redox Chemistry and Ubiquitylation: Post-Translational Modifications Required for Maintaining Cellular Homeostasis and Neuroprotection

by Emma I. Kane, Kelly L. Waters and Donald E. Spratt

Cells 2021, 10(8), 2121; https://doi.org/10.3390/cells10082121 - 18 Aug 2021

Cited by 2 | Viewed by 2184

Abstract

Neurodegeneration has been predominantly recognized as neuronal breakdown induced by the accumulation of aggregated and/or misfolded proteins and remains a preliminary factor in age-dependent disease. Recently, critical regulating molecular mechanisms and cellular pathways have been shown to induce neurodegeneration long before aggregate accumulation could occur. Although this opens the possibility of identifying biomarkers for early onset diagnosis, many of these pathways vary in their modes of dysfunction while presenting similar clinical phenotypes. With selectivity remaining difficult, it is promising that these neuroprotective pathways are regulated through the ubiquitin-proteasome system (UPS). This essential post-translational modification (PTM) involves the specific attachment of ubiquitin onto a substrate, specifically marking the ubiquitin-tagged protein for its intracellular fate based upon the site of attachment, the ubiquitin chain type built, and isopeptide linkages between different ubiquitin moieties. This review highlights both the direct and indirect impact ubiquitylation has in oxidative stress response and neuroprotection, and how irregularities in these intricate processes lead towards the onset of neurodegenerative disease (NDD). Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)

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30 pages, 1286 KiB

Open AccessReview

Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders

by Adrian Mor, Anna Tankiewicz-Kwedlo, Anna Krupa and Dariusz Pawlak

Cells 2021, 10(7), 1603; https://doi.org/10.3390/cells10071603 - 26 Jun 2021

Cited by 51 | Viewed by 4794

Abstract

Neurodegenerative disorders are chronic and life-threatening conditions negatively affecting the quality of patients’ lives. They often have a genetic background, but oxidative stress and mitochondrial damage seem to be at least partly responsible for their development. Recent reports indicate that the activation of the kynurenine pathway (KP), caused by an activation of proinflammatory factors accompanying neurodegenerative processes, leads to the accumulation of its neuroactive and pro-oxidative metabolites. This leads to an increase in the oxidative stress level, which increases mitochondrial damage, and disrupts the cellular energy metabolism. This significantly reduces viability and impairs the proper functioning of central nervous system cells and may aggravate symptoms of many psychiatric and neurodegenerative disorders. This suggests that the modulation of KP activity could be effective in alleviating these symptoms. Numerous reports indicate that tryptophan supplementation, inhibition of KP enzymes, and administration or analogs of KP metabolites show promising results in the management of neurodegenerative disorders in animal models. This review gathers and systematizes the knowledge concerning the role of metabolites and enzymes of the KP in the development of oxidative damage within brain cells during neurodegenerative disorders and potential strategies that could reduce the severity of this process. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)

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