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Epigenetic Mechanisms of 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 Neurobiology".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 7284

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Special Issue Editor

Dr. Alessandro Ieraci

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Guest Editor

Department of Pharmaceutical Sciences, University of Milan, Via Balzaretti 9, 20133 Milano, Italy
Interests: psychiatric disorders; neurodegenerative diseases; stress; physical exercise; neurotrophins; epigenetic mechanisms; inflammation; animal models

Special Issue Information

Dear Colleagues,

Over the past few years, accumulating evidence has suggested that epigenetic mechanisms, such as DNA methylation, histone post-translational modifications, and miRNAs, can play an important role in a variety of processes related to aging, including neurodegenerative diseases. Epigenetic mechanisms are finely regulated and influenced by multiple environmental factors throughout the lifespan. Contrary to genetic alterations, epigenetic modifications are reversible and may therefore be a promising target for new therapeutic strategies.

Neurodegenerative diseases, such as Alzheimer’s disease, Huntington’s disease, multiple sclerosis, and amyotrophic lateral sclerosis, are debilitating and incurable conditions affecting millions of people worldwide. Although the etiopathogenesis of neurodegenerative diseases is not well known yet, they share some common features, including transcriptional dysregulation. However, the mechanisms underlying the epigenetic alterations in the development of neurodegenerative diseases are still poorly understood.

In this Special Issue, we aim at collecting original as well as review papers that provide state-of-the-art insight into the role of epigenetic mechanisms in the context of neurodegenerative diseases. Papers analyzing environmental factors (diet, stress, pollution, pathogen infection, exercise, etc.) affecting epigenetic mechanisms and neurodegenerative diseases will be particularly welcome.

Dr. Alessandro Ieraci
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

DNA methylation
histone modification
miRNA
transcriptional dysregulation
epigenetic mechanisms
neurodegeneration
neuronal cell death

Published Papers (4 papers)

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Research

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12 pages, 1446 KiB

Open AccessArticle

Differential Epigenetic Changes in the Dorsal Hippocampus of Male and Female SAMP8 Mice: A Preliminary Study

by Federico Ravanelli, Laura Musazzi, Silvia Stella Barbieri, Gianenrico Rovati, Maurizio Popoli, Alessandro Barbon and Alessandro Ieraci

Int. J. Mol. Sci. 2023, 24(17), 13084; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241713084 - 23 Aug 2023

Cited by 2 | Viewed by 905

Abstract

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease characterized by memory loss and cognitive impairment. The causes of the disease are not well understood, as it involves a complex interaction between genetic, environmental, and epigenetic factors. SAMP8 mice have been proposed as a model for studying late-onset AD, since they show age-related learning and memory deficits as well as several features of AD pathogenesis. Epigenetic changes have been described in SAMP8 mice, although sex differences have never been evaluated. Here we used western blot and qPCR analyses to investigate whether epigenetic markers are differentially altered in the dorsal hippocampus, a region important for the regulation of learning and memory, of 9-month-old male and female SAMP8 mice. We found that H3Ac was selectively reduced in male SAMP8 mice compared to male SAMR1 control mice, but not in female mice, whereas H3K27me3 was reduced overall in SAMP8 mice. Moreover, the levels of HDAC2 and JmjD3 were increased, whereas the levels of HDAC4 and Dnmt3a were reduced in SAMP8 mice compared to SAMR1. In addition, levels of HDAC1 were reduced, whereas Utx and Jmjd3 were selectively increased in females compared to males. Although our results are preliminary, they suggest that epigenetic mechanisms in the dorsal hippocampus are differentially regulated in male and female SAMP8 mice. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Neurodegenerative Diseases)

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23 pages, 2915 KiB

Open AccessArticle

Acetylation State of Lysine 14 of Histone H3.3 Affects Mutant Huntingtin Induced Pathogenesis

by Anikó Faragó, Nóra Zsindely, Anita Farkas, Alexandra Neller, Fruzsina Siági, Márton Richárd Szabó, Tamás Csont and László Bodai

Int. J. Mol. Sci. 2022, 23(23), 15173; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315173 - 2 Dec 2022

Cited by 4 | Viewed by 1767

Abstract

Huntington’s Disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a polyglutamine-coding CAG repeat in the Huntingtin gene. One of the main causes of neurodegeneration in HD is transcriptional dysregulation that, in part, is caused by the inhibition of histone acetyltransferase (HAT) enzymes. HD pathology can be alleviated by increasing the activity of specific HATs or by inhibiting histone deacetylase (HDAC) enzymes. To determine which histone’s post-translational modifications (PTMs) might play crucial roles in HD pathology, we investigated the phenotype-modifying effects of PTM mimetic mutations of variant histone H3.3 in a Drosophila model of HD. Specifically, we studied the mutations (K→Q: acetylated; K→R: non-modified; and K→M: methylated) of lysine residues K9, K14, and K27 of transgenic H3.3. In the case of H3.3K14Q modification, we observed the amelioration of all tested phenotypes (viability, longevity, neurodegeneration, motor activity, and circadian rhythm defects), while H3.3K14R had the opposite effect. H3.3K14Q expression prevented the negative effects of reduced Gcn5 (a HAT acting on H3K14) on HD pathology, while it only partially hindered the positive effects of heterozygous Sirt1 (an HDAC acting on H3K14). Thus, we conclude that the Gcn5-dependent acetylation of H3.3K14 might be an important epigenetic contributor to HD pathology. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Neurodegenerative Diseases)

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18 pages, 1961 KiB

Open AccessArticle

Identification of Epigenetic Interactions between MicroRNA-30c-5p and DNA Methyltransferases in Neuropathic Pain

by Raquel Francés, Jorge Mata-Garrido, Roberto de la Fuente, María Carcelén, Miguel Lafarga, María Teresa Berciano, Raquel García, María A. Hurlé and Mónica Tramullas

Int. J. Mol. Sci. 2022, 23(22), 13994; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232213994 - 13 Nov 2022

Cited by 5 | Viewed by 1473

Abstract

Neuropathic pain is a prevalent and severe chronic syndrome, often refractory to treatment, whose development and maintenance may involve epigenetic mechanisms. We previously demonstrated a causal relationship between miR-30c-5p upregulation in nociception-related neural structures and neuropathic pain in rats subjected to sciatic nerve injury. Furthermore, a short course of an miR-30c-5p inhibitor administered into the cisterna magna exerts long-lasting antiallodynic effects via a TGF-β1-mediated mechanism. Herein, we show that miR-30c-5p inhibition leads to global DNA hyper-methylation of neurons in the lumbar dorsal root ganglia and spinal dorsal horn in rats subjected to sciatic nerve injury. Specifically, the inhibition of miR-30-5p significantly increased the expression of the novo DNA methyltransferases DNMT3a and DNMT3b in those structures. Furthermore, we identified the mechanism and found that miR-30c-5p targets the mRNAs of DNMT3a and DNMT3b. Quantitative methylation analysis revealed that the promoter region of the antiallodynic cytokine TGF-β1 was hypomethylated in the spinal dorsal horn of nerve-injured rats treated with the miR-30c-5p inhibitor, while the promoter of Nfyc, the host gene of miR-30c-5p, was hypermethylated. These results are consistent with long-term protection against neuropathic pain development after nerve injury. Altogether, our results highlight the key role of miR-30c-5p in the epigenetic mechanisms’ underlying neuropathic pain and provide the basis for miR-30c-5p as a therapeutic target. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Neurodegenerative Diseases)

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Review

Jump to: Research

35 pages, 1578 KiB

Open AccessReview

RNA-Binding Proteins as Epigenetic Regulators of Brain Functions and Their Involvement in Neurodegeneration

by Carlo Maria Di Liegro, Gabriella Schiera, Giuseppe Schirò and Italia Di Liegro

Int. J. Mol. Sci. 2022, 23(23), 14622; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314622 - 23 Nov 2022

Cited by 3 | Viewed by 2521

Abstract

A central aspect of nervous system development and function is the post-transcriptional regulation of mRNA fate, which implies time- and site-dependent translation, in response to cues originating from cell-to-cell crosstalk. Such events are fundamental for the establishment of brain cell asymmetry, as well as of long-lasting modifications of synapses (long-term potentiation: LTP), responsible for learning, memory, and higher cognitive functions. Post-transcriptional regulation is in turn dependent on RNA-binding proteins that, by recognizing and binding brief RNA sequences, base modifications, or secondary/tertiary structures, are able to control maturation, localization, stability, and translation of the transcripts. Notably, most RBPs contain intrinsically disordered regions (IDRs) that are thought to be involved in the formation of membrane-less structures, probably due to liquid–liquid phase separation (LLPS). Such structures are evidenced as a variety of granules that contain proteins and different classes of RNAs. The other side of the peculiar properties of IDRs is, however, that, under altered cellular conditions, they are also prone to form aggregates, as observed in neurodegeneration. Interestingly, RBPs, as part of both normal and aggregated complexes, are also able to enter extracellular vesicles (EVs), and in doing so, they can also reach cells other than those that produced them. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Neurodegenerative Diseases)

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