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Epigenetics in Neurodegenerative Diseases

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

Deadline for manuscript submissions: closed (10 August 2023) | Viewed by 19297

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Dr. Roberta Mancuso

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IRCCS Fondazione Don Carlo Gnocchi, 20162 Milan, Italy
Interests: human viruses; immunity; humoral response; Alzheimer’s disease; multiple sclerosis; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals

Dr. Simone Agostini

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Institution of IRCCS Fondazione Don Carlo Gnocchi (Laboratorio di Medicina Molecolare e Biotech), 20162 Milan, Italy
Interests: human viruses; immunity; antibody; Alzheimer’s disease; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recently, epigenetics—the study of the modification of gene expression that does not involve a change in the DNA sequence—has rapidly become established as a major topic in molecular biology and genetics. The two major components of epigenetics are DNA methylation and histone modifications. Additionally, microRNA (miRNAs), short molecules of RNA, are able to post-transcriptionally modulate their target mRNA and are key molecules for the normal control of gene expression. Epigenetic modifications have an important impact on human health and constitute an area of great interest for the study of several diseases, in particular multifactorial diseases. Neurodegenerative diseases, such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis, are complex diseases often with unknown pathogeneses. The interactions among different factors—genetics, inflammation, environmental—play a role in their development and progression. For these reasons, the present Special Issue focuses on 1) DNA methylation; 2) histone modification; and 3) miRNA expressions in neurodegenerative diseases to better understand the molecular and biological mechanisms deregulated in these pathologies, which will lead to new roads of promising pharmacological and clinical therapies. Research articles (clinical studies with molecular experiments, in vitro studies and disease vs. control studies) as well as reviews are welcomed for this Special Issue.

Dr. Roberta Mancuso
Dr. Simone Agostini
Guest Editors

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Keywords

epigenetics
miRNAs
DNA methylation
histone modification
sclerosis multiple
Alzheimer’s disease
Parkinson’s disease
amyotrophic lateral sclerosis

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 171 KiB

Open AccessEditorial

Special Issue “Epigenetics in Neurodegenerative Diseases”

by Simone Agostini and Roberta Mancuso

Int. J. Mol. Sci. 2024, 25(7), 3647; https://doi.org/10.3390/ijms25073647 - 25 Mar 2024

Viewed by 498

Abstract

Epigenetic mechanisms inducing phenotypic changes without altering the DNA genome are increasingly recognized as key factors modulating gene expression and, consequently, cell functions [...] Full article

(This article belongs to the Special Issue Epigenetics in Neurodegenerative Diseases)

Research

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16 pages, 3172 KiB

Open AccessArticle

Cell Cycle Reactivation, at the Start of Neurodegeneration, Induced by Forskolin and Aniline in Differentiated Neuroblastoma Cells

by Valentina Sturiale, Francesca Bruno, Desiree Brancato, Agata Grazia D’Amico, Grazia Maugeri, Velia D’Agata, Salvatore Saccone and Concetta Federico

Int. J. Mol. Sci. 2023, 24(18), 14373; https://doi.org/10.3390/ijms241814373 - 21 Sep 2023

Viewed by 753

Abstract

A characteristic hallmark of Alzheimer’s disease (AD) is the intracellular accumulation of hyperphosphorylated tau protein, a phenomenon that appears to have associations with oxidative stress, double-stranded DNA breakage, and the de-condensation of heterochromatin. Re-entry into the cell division cycle appears to be involved in the onset of this neurodegenerative process. Indeed, the cell cycle cannot proceed regularly in the differentiated neurons leading to cell death. Here, we induced cell cycle reactivation in neuronal-like cells, obtained by neuroblastoma cells treated with retinoic acid, by exposure to forskolin or aniline. These compounds determine tau hyperphosphorylation or oxidative stress, respectively, resulting in the appearance of features resembling the start of neuronal degeneration typical of AD, such as tau hyperphosphorylation and re-entry into the cell cycle. Indeed, we detected an increased transcriptional level of cyclins and the appearance of a high number of mitotic cells. We also observed a delay in the initiation of the cell cycle when forskolin was co-administered with pituitary adenylate cyclase-activating polypeptide (PACAP). This delay was not observed when PACAP was co-administered with aniline. Our data demonstrate the relevance of tau hyperphosphorylation in initiating an ectopic cell cycle in differentiated neuronal cells, a condition that can lead to neurodegeneration. Moreover, we highlight the utility of neuroblastoma cell lines as an in vitro cellular model to test the possible neuroprotective effects of natural molecules. Full article

(This article belongs to the Special Issue Epigenetics in Neurodegenerative Diseases)

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13 pages, 1839 KiB

Open AccessArticle

Association between the Cytosine Hydroxymethylation and the Expression of microRNA in Multiple Sclerosis in Polish Population

by Justyna Basak, Danuta Piotrzkowska, Aleksandra Kucharska-Lusina and Ireneusz Majsterek

Int. J. Mol. Sci. 2023, 24(18), 13923; https://doi.org/10.3390/ijms241813923 - 10 Sep 2023

Cited by 1 | Viewed by 933

Abstract

Multiple sclerosis is a chronic demyelinating disorder with an unclear etiology. A key role is thought to be played by Th17 cells and microRNAs associated with Th17, such as miR-155, miR-326 and miR-223. The present study compared the methylation and hydroxymethylation levels of CpG sites within promoters of these microRNA between MS patients and controls using PBMCs and analyzed their relationship with microRNA expression. Significant intergroup differences were found between the levels of 5-hmC within the CpG-1 miR-155 promoter and CpG within the miR-326 promoter; in addition, miR-155-5p and miR-223-3p expression was elevated in MS patients. Correlation analysis showed a positive relationship between the level of 5-hmC of CpG-2 in the miR-223 promoter and miR-223-3p level. As it is possible to pharmacologically modulate the level of epigenetic modifications, our findings cast light on the etiology of MS and support the development of more effective therapies. Full article

(This article belongs to the Special Issue Epigenetics in Neurodegenerative Diseases)

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21 pages, 8037 KiB

Open AccessArticle

5-Methylcytosine and 5-Hydroxymethylcytosine in Scrapie-Infected Sheep and Mouse Brain Tissues

by Adelaida Hernaiz, Sara Sentre, Marina Betancor, Óscar López-Pérez, Mónica Salinas-Pena, Pilar Zaragoza, Juan José Badiola, Janne Markus Toivonen, Rosa Bolea and Inmaculada Martín-Burriel

Int. J. Mol. Sci. 2023, 24(2), 1621; https://doi.org/10.3390/ijms24021621 - 13 Jan 2023

Cited by 1 | Viewed by 1590

Abstract

Scrapie is a neurodegenerative disorder belonging to the group of transmissible spongiform encephalopathies or prion diseases, which are caused by an infectious isoform of the innocuous cellular prion protein (PrP^C) known as PrP^Sc. DNA methylation, one of the most studied epigenetic mechanisms, is essential for the proper functioning of the central nervous system. Recent findings point to possible involvement of DNA methylation in the pathogenesis of prion diseases, but there is still a lack of knowledge about the behavior of this epigenetic mechanism in such neurodegenerative disorders. Here, we evaluated by immunohistochemistry the 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels in sheep and mouse brain tissues infected with scrapie. Expression analysis of different gene coding for epigenetic regulatory enzymes (DNMT1, DNMT3A, DNMT3B, HDAC1, HDAC2, TET1, and TET2) was also carried out. A decrease in 5mC levels was observed in scrapie-affected sheep and mice compared to healthy animals, whereas 5hmC displayed opposite patterns between the two models, demonstrating a decrease in 5hmC in scrapie-infected sheep and an increase in preclinical mice. 5mC correlated with prion-related lesions in mice and sheep, but 5hmC was associated with prion lesions only in sheep. Differences in the expression changes of epigenetic regulatory genes were found between both disease models, being differentially expressed Dnmt3b, Hdac1, and Tet1 in mice and HDAC2 in sheep. Our results support the evidence that DNA methylation in both forms, 5mC and 5hmC, and its associated epigenetic enzymes, take part in the neurodegenerative course of prion diseases. Full article

(This article belongs to the Special Issue Epigenetics in Neurodegenerative Diseases)

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19 pages, 2738 KiB

Open AccessArticle

The Role of Bromodomain and Extraterminal (BET) Proteins in Controlling the Phagocytic Activity of Microglia In Vitro: Relevance to Alzheimer’s Disease

by Marta Matuszewska, Magdalena Cieślik, Anna Wilkaniec, Marcin Strawski and Grzegorz A. Czapski

Int. J. Mol. Sci. 2023, 24(1), 13; https://doi.org/10.3390/ijms24010013 - 20 Dec 2022

Cited by 4 | Viewed by 2036

Abstract

The correct phagocytic activity of microglia is a prerequisite for maintaining homeostasis in the brain. In the analysis of mechanisms regulating microglial phagocytosis, we focused on the bromodomain and extraterminal domain (BET) proteins: Brd2, Brd3, and Brd4, the acetylation code readers that control gene expression in cooperation with transcription factors. We used pharmacological (JQ1) and genetic (siRNA) inhibition of BET proteins in murine microglial cell line BV2. Inhibition of BET proteins reduced the phagocytic activity of BV2, as determined by using a fluorescent microspheres-based assay and fluorescently labelled amyloid-beta peptides. Gene silencing experiments demonstrated that all brain-existing BET isoforms control phagocytosis in microglia. From a set of 84 phagocytosis-related genes, we have found the attenuation of the expression of 14: Siglec1, Sirpb1a, Cd36, Clec7a, Itgam, Tlr3, Fcgr1, Cd14, Marco, Pld1, Fcgr2b, Anxa1, Tnf, Nod1, upon BET inhibition. Further analysis of the mRNA level of other phagocytosis-related genes which were involved in the pathomechanism of Alzheimer’s disease demonstrated that JQ1 significantly reduced the expression of Cd33, Trem2, and Zyx. Our results indicate the important role of BET proteins in controlling microglial phagocytosis; therefore, targeting BET may be the efficient method of modulating microglial activity. Full article

(This article belongs to the Special Issue Epigenetics in Neurodegenerative Diseases)

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14 pages, 2164 KiB

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The Epigenetic Role of miR-124 in HIV-1 Tat- and Cocaine-Mediated Microglial Activation

by Palsamy Periyasamy, Annadurai Thangaraj, Muthukumar Kannan, Abiola Oladapo and Shilpa Buch

Int. J. Mol. Sci. 2022, 23(23), 15017; https://doi.org/10.3390/ijms232315017 - 30 Nov 2022

Cited by 3 | Viewed by 1584

Abstract

HIV-1 and drug abuse have been indissolubly allied as entwined epidemics. It is well-known that drug abuse can hasten the progression of HIV-1 and its consequences, especially in the brain, causing neuroinflammation. This study reports the combined effects of HIV-1 Transactivator of Transcription (Tat) protein and cocaine on miR-124 promoter DNA methylation and its role in microglial activation and neuroinflammation. The exposure of mouse primary microglial cells to HIV-1 Tat (25 ng/mL) and/or cocaine (10 μM) resulted in the significantly decreased expression of primary (pri)-miR-124-1, pri-miR-124-2, and mature miR-124 with a concomitant upregulation in DNMT1 expression as well as global DNA methylation. Our bisulfite-converted genomic DNA sequencing also revealed significant promoter DNA methylation in the pri-miR-124-1 and pri-miR-124-2 in HIV-1 Tat- and cocaine-exposed mouse primary microglial cells. We also found the increased expression of proinflammatory cytokines such as IL1β, IL6 and TNF in the mouse primary microglia exposed to HIV-1 Tat and cocaine correlated with microglial activation. Overall, our findings demonstrate that the exposure of mouse primary microglia to both HIV-1 Tat and cocaine could result in intensified microglial activation via the promoter DNA hypermethylation of miR-124, leading to the exacerbated release of proinflammatory cytokines, ultimately culminating in neuroinflammation. Full article

(This article belongs to the Special Issue Epigenetics in Neurodegenerative Diseases)

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13 pages, 6153 KiB

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Circulating Non-Coding RNA Levels Are Altered in Autosomal Dominant Frontotemporal Dementia

by Chiara Fenoglio, Maria Serpente, Caterina Visconte, Marina Arcaro, Federica Sorrentino, Marianna D’Anca, Andrea Arighi, Emanuela Rotondo, Roberto Vimercati, Giacomina Rossi, Elio Scarpini and Daniela Galimberti

Int. J. Mol. Sci. 2022, 23(23), 14723; https://doi.org/10.3390/ijms232314723 - 25 Nov 2022

Viewed by 1443

Abstract

Frontotemporal Dementia (FTD) represents a highly heritable neurodegenerative disorder. Most of the heritability is caused by autosomal dominant mutations in the Microtubule-Associated Protein Tau (MAPT), Progranulin (GRN), and the pathologic exanucleotide expansion of C9ORF72 genes. At the pathological level, either the tau or the TAR DNA-binding protein (TDP-43) account for almost all cases of FTD. Pathogenic mechanisms are just arising, and the emerging role of non-coding RNAs (ncRNAs), such as microRNAs (miRNA) and long non-coding RNAs (lncRNAs), have become increasingly evident. Using specific arrays, an exploratory analysis testing the expression levels of 84 miRNAs and 84 lncRNAs has been performed in a population consisting of 24 genetic FTD patients (eight GRN, eight C9ORF72, and eight MAPT mutation carriers), eight sporadic FTD patients, and eight healthy controls. The results showed a generalized ncRNA downregulation in patients carrying GRN and C9ORF72 when compared with the controls, with statistically significant results for the following miRNAs: miR-155-5p (Fold Change FC: 0.45, p = 0.037 FDR = 0.52), miR-15a-5p (FC: 0.13, p = 0.027, FDR = 1), miR-222-3p (FC: 0.13, p = 0.027, FDR = 0.778), miR-140-3p (FC: 0.096, p = 0.034, FRD = 0.593), miR-106b-5p (FC: 0.13, p = 0.02, FDR = 0.584) and an upregulation solely for miR-124-3p (FC: 2.1, p = 0.01, FDR = 0.893). Conversely, MAPT mutation carriers showed a generalized robust upregulation in several ncRNAs, specifically for miR-222-3p (FC: 22.3, p = 7 × 10⁻⁶, FDR = 0.117), miR-15a-5p (FC: 30.2, p = 0.008, FDR = 0.145), miR-27a-3p (FC: 27.8, p = 6 × 10⁻⁶, FDR = 0.0005), miR-223-3p (FC: 18.9, p = 0.005, FDR = 0.117), and miR-16-5p (FC: 10.9, p = 5.26 × 10⁻⁵, FDR = 0.001). These results suggest a clear, distinctive pattern of dysregulation among ncRNAs and specific enrichment gene pathways between mutations associated with the TDP-43 and tau pathologies. Nevertheless, these preliminary results need to be confirmed in a larger independent cohort. Full article

(This article belongs to the Special Issue Epigenetics in Neurodegenerative Diseases)

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Review

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51 pages, 5766 KiB

Open AccessReview

TDP-43 Epigenetic Facets and Their Neurodegenerative Implications

by Juliette Gimenez, Alida Spalloni, Sara Cappelli, Francesca Ciaiola, Valerio Orlando, Emanuele Buratti and Patrizia Longone

Int. J. Mol. Sci. 2023, 24(18), 13807; https://doi.org/10.3390/ijms241813807 - 7 Sep 2023

Viewed by 2091

Abstract

Since its initial involvement in numerous neurodegenerative pathologies in 2006, either as a principal actor or as a cofactor, new pathologies implicating transactive response (TAR) DNA-binding protein 43 (TDP-43) are regularly emerging also beyond the neuronal system. This reflects the fact that TDP-43 functions are particularly complex and broad in a great variety of human cells. In neurodegenerative diseases, this protein is often pathologically delocalized to the cytoplasm, where it irreversibly aggregates and is subjected to various post-translational modifications such as phosphorylation, polyubiquitination, and cleavage. Until a few years ago, the research emphasis has been focused particularly on the impacts of this aggregation and/or on its widely described role in complex RNA splicing, whether related to loss- or gain-of-function mechanisms. Interestingly, recent studies have strengthened the knowledge of TDP-43 activity at the chromatin level and its implication in the regulation of DNA transcription and stability. These discoveries have highlighted new features regarding its own transcriptional regulation and suggested additional mechanistic and disease models for the effects of TPD-43. In this review, we aim to give a comprehensive view of the potential epigenetic (de)regulations driven by (and driving) this multitask DNA/RNA-binding protein. Full article

(This article belongs to the Special Issue Epigenetics in Neurodegenerative Diseases)

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17 pages, 796 KiB

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Minor Changes for a Major Impact: A Review of Epigenetic Modifications in Cell-Based Therapies for Stroke

by Molly Monsour, Jonah Gordon, Gavin Lockard, Adam Alayli, Bassel Elsayed, Jacob Connolly and Cesar V. Borlongan

Int. J. Mol. Sci. 2022, 23(21), 13106; https://doi.org/10.3390/ijms232113106 - 28 Oct 2022

Cited by 1 | Viewed by 1840

Abstract

Epigenetic changes in stroke may revolutionize cell-based therapies aimed at reducing ischemic stroke risk and damage. Epigenetic changes are a novel therapeutic target due to their specificity and potential for reversal. Possible targets for epigenetic modification include DNA methylation and demethylation, post-translational histone modification, and the actions of non-coding RNAs such as microRNAs. Many of these epigenetic modifications have been reported to modulate atherosclerosis development and progression, ultimately contributing to stroke pathogenesis. Furthermore, epigenetics may play a major role in inflammatory responses following stroke. Stem cells for stroke have demonstrated safety in clinical trials for stroke and show therapeutic benefit in pre-clinical studies. The efficacy of these cell-based interventions may be amplified with adjunctive epigenetic modifications. This review advances the role of epigenetics in atherosclerosis and inflammation in the context of stroke, followed by a discussion on current stem cell studies modulating epigenetics to ameliorate stroke damage. Full article

(This article belongs to the Special Issue Epigenetics in Neurodegenerative Diseases)

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28 pages, 1003 KiB

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Epigenetic Changes in Prion and Prion-like Neurodegenerative Diseases: Recent Advances, Potential as Biomarkers, and Future Perspectives

by Adelaida Hernaiz, Janne Markus Toivonen, Rosa Bolea and Inmaculada Martín-Burriel

Int. J. Mol. Sci. 2022, 23(20), 12609; https://doi.org/10.3390/ijms232012609 - 20 Oct 2022

Cited by 11 | Viewed by 2677

Abstract

Prion diseases are transmissible spongiform encephalopathies (TSEs) caused by a conformational conversion of the native cellular prion protein (PrP^C) to an abnormal, infectious isoform called PrP^Sc. Amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s diseases are also known as prion-like diseases because they share common features with prion diseases, including protein misfolding and aggregation, as well as the spread of these misfolded proteins into different brain regions. Increasing evidence proposes the involvement of epigenetic mechanisms, namely DNA methylation, post-translational modifications of histones, and microRNA-mediated post-transcriptional gene regulation in the pathogenesis of prion-like diseases. Little is known about the role of epigenetic modifications in prion diseases, but recent findings also point to a potential regulatory role of epigenetic mechanisms in the pathology of these diseases. This review highlights recent findings on epigenetic modifications in TSEs and prion-like diseases and discusses the potential role of such mechanisms in disease pathology and their use as potential biomarkers. Full article

(This article belongs to the Special Issue Epigenetics in Neurodegenerative Diseases)

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22 pages, 410 KiB

Open AccessReview

Non-Pharmacological Therapeutic Options for the Treatment of Alzheimer’s Disease

by Quy-Susan Huynh, Shalini Elangovan and R. M. Damian Holsinger

Int. J. Mol. Sci. 2022, 23(19), 11037; https://doi.org/10.3390/ijms231911037 - 20 Sep 2022

Cited by 5 | Viewed by 2661

Abstract

Alzheimer’s disease is a growing global crisis in need of urgent diagnostic and therapeutic strategies. The current treatment strategy mostly involves immunotherapeutic medications that have had little success in halting disease progress. Hypotheses for pathogenesis and development of AD have been expanded to implicate both organ systems as well as cellular reactions. Non-pharmacologic interventions ranging from minimally to deeply invasive have attempted to address these diverse contributors to AD. In this review, we aim to delineate mechanisms underlying such interventions while attempting to provide explanatory links between the observed differences in disease states and postulated metabolic or structural mechanisms of change. The techniques discussed are not an exhaustive list of non-pharmacological interventions against AD but provide a foundation to facilitate a deeper understanding of the area of study. Full article

(This article belongs to the Special Issue Epigenetics in Neurodegenerative Diseases)

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