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Epigenetic Regulation in Neurodegeneration Disease
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Epigenetic Regulation in Neurodegeneration Disease

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 (31 October 2021) | Viewed by 24367

Special Issue Editor

Dr. Laszlo Bodai

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
Interests: molecular pathogenesis of neurodegeneration; Huntington’s disease; Alzheimer’s disease; transcriptomics; miRNAs; epigenetic regulation of transcription; histone variants and histone modifications; animal models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegeneration disorders are devastating diseases that cause symptoms ranging from movement and psychiatric disturbances to cognitive decline and might have fatal consequences. Despite decades of intensive research, an effective cure is not available for most neurodegenerative diseases; therefore, a better understanding of the molecular basis of their pathogenesis is imperative. Despite the diversity of affected brain structures and the multifaceted pathogenesis, some pathological processes seem to be common for several neurodegenerative disorders. One of these pathogenic mechanisms is epigenetic dysregulation, an alteration in the structure and functional state of chromatin that can be the consequence of altered DNA methylation patterns, or dysregulated histone post-translational modifications, among others. As the state of chromatin regulates all DNA-templated processes, including gene transcription, it has widespread effects on various cellular mechanisms. The aim of this Special Issue is to shed light on recent advances in research into the epigenetic background of neurodegenerative disorders and the potential applicability of epigenetic therapy. For this Special Issue, we welcome the following manuscript categories: original scientific research articles, short communications, and review articles.

Dr. Laszlo Bodai
Guest Editor

Manuscript Submission Information

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Keywords

  • neurodegeneration 
  • neurodegenerative disorders 
  • Alzheimer’s disease 
  • Parkinson’s disease 
  • polyglutamine diseases 
  • epigenetics 
  • chromatin 
  • histone modifications 
  • DNA methylation 
  • chromatin remodeling

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Published Papers (6 papers)

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Editorial

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3 pages, 208 KiB  
Editorial
Epigenetic Regulation in Neurodegeneration Disease
by László Bodai
Int. J. Mol. Sci. 2022, 23(11), 6185; https://doi.org/10.3390/ijms23116185 - 31 May 2022
Cited by 1 | Viewed by 1475
Abstract
Due to their often age-dependent nature, neurodegenerative diseases impact an increasing portion of modern societies [...] Full article
(This article belongs to the Special Issue Epigenetic Regulation in Neurodegeneration Disease)

Research

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20 pages, 4417 KiB  
Article
Beneficial and Sexually Dimorphic Response to Combined HDAC Inhibitor Valproate and AMPK/SIRT1 Pathway Activator Resveratrol in the Treatment of ALS Mice
by Oluwamolakun Bankole, Ilaria Scambi, Edoardo Parrella, Matilde Muccilli, Roberta Bonafede, Ermanna Turano, Marina Pizzi and Raffaella Mariotti
Int. J. Mol. Sci. 2022, 23(3), 1047; https://doi.org/10.3390/ijms23031047 - 19 Jan 2022
Cited by 12 | Viewed by 3534
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There is no cure and current treatments fail to slow the progression of the disease. Epigenetic modulation in the acetylation state of NF-kB RelA and the histone 3 (H3) protein, involved in the [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There is no cure and current treatments fail to slow the progression of the disease. Epigenetic modulation in the acetylation state of NF-kB RelA and the histone 3 (H3) protein, involved in the development of neurodegeneration, is a drugable target for the class-I histone deacetylases (HDAC) inhibitors, entinostat or valproate, and the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator, resveratrol. In this study, we demonstrated that the combination of valproate and resveratrol can restore the normal acetylation state of RelA in the SOD1(G93A) murine model of ALS, in order to obtain the neuroprotective form of NF-kB. We also investigated the sexually dimorphic development of the disease, as well as the sex-sensibility to the treatment administered. We showed that the combined drugs, which rescued AMPK activation, RelA and the histone 3 acetylation state, reduced the motor deficit and the disease pathology associated with motor neuron loss and microglial reactivity, Brain-Derived Neurotrophic Factor (BDNF) and B-cell lymphoma-extra large (Bcl-xL) level decline. Specifically, vehicle-administered males showed earlier onset and slower progression of the disease when compared to females. The treatment, administered at 50 days of life, postponed the time of onset in the male by 22 days, but not in a significant way in females. Nevertheless, in females, the drugs significantly reduced symptom severity of the later phase of the disease and prolonged the mice’s survival. Only minor beneficial effects were produced in the latter stage in males. Overall, this study shows a beneficial and sexually dimorphic response to valproate and resveratrol treatment in ALS mice. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Neurodegeneration Disease)
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19 pages, 3987 KiB  
Article
Knock-Down of HDAC2 in Human Induced Pluripotent Stem Cell Derived Neurons Improves Neuronal Mitochondrial Dynamics, Neuronal Maturation and Reduces Amyloid Beta Peptides
by Harald Frankowski, Fred Yeboah, Bonnie J. Berry, Chizuru Kinoshita, Michelle Lee, Kira Evitts, Joshua Davis, Yoshito Kinoshita, Richard S. Morrison and Jessica E. Young
Int. J. Mol. Sci. 2021, 22(5), 2526; https://doi.org/10.3390/ijms22052526 - 3 Mar 2021
Cited by 8 | Viewed by 3627
Abstract
Histone deacetylase 2 (HDAC2) is a major HDAC protein in the adult brain and has been shown to regulate many neuronal genes. The aberrant expression of HDAC2 and subsequent dysregulation of neuronal gene expression is implicated in neurodegeneration and brain aging. Human induced [...] Read more.
Histone deacetylase 2 (HDAC2) is a major HDAC protein in the adult brain and has been shown to regulate many neuronal genes. The aberrant expression of HDAC2 and subsequent dysregulation of neuronal gene expression is implicated in neurodegeneration and brain aging. Human induced pluripotent stem cell-derived neurons (hiPSC-Ns) are widely used models for studying neurodegenerative disease mechanisms, but the role of HDAC2 in hiPSC-N differentiation and maturation has not been explored. In this study, we show that levels of HDAC2 progressively decrease as hiPSCs are differentiated towards neurons. This suppression of HDAC2 inversely corresponds to an increase in neuron-specific isoforms of Endophilin-B1, a multifunctional protein involved in mitochondrial dynamics. Expression of neuron-specific isoforms of Endophilin-B1 is accompanied by concomitant expression of a neuron-specific alternative splicing factor, SRRM4. Manipulation of HDAC2 and Endophilin-B1 using lentiviral approaches shows that the knock-down of HDAC2 or the overexpression of a neuron-specific Endophilin-B1 isoform promotes mitochondrial elongation and protects against cytotoxic stress in hiPSC-Ns, while HDAC2 knock-down specifically influences genes regulating mitochondrial dynamics and synaptogenesis. Furthermore, HDAC2 knock-down promotes enhanced mitochondrial respiration and reduces levels of neurotoxic amyloid beta peptides. Collectively, our study demonstrates a role for HDAC2 in hiPSC-neuronal differentiation, highlights neuron-specific isoforms of Endophilin-B1 as a marker of differentiating hiPSC-Ns and demonstrates that HDAC2 regulates key neuronal and mitochondrial pathways in hiPSC-Ns. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Neurodegeneration Disease)
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20 pages, 3685 KiB  
Article
Nuclear Reorganization in Hippocampal Granule Cell Neurons from a Mouse Model of Down Syndrome: Changes in Chromatin Configuration, Nucleoli and Cajal Bodies
by Alba Puente-Bedia, María T. Berciano, Olga Tapia, Carmen Martínez-Cué, Miguel Lafarga and Noemí Rueda
Int. J. Mol. Sci. 2021, 22(3), 1259; https://doi.org/10.3390/ijms22031259 - 27 Jan 2021
Cited by 8 | Viewed by 3217
Abstract
Down syndrome (DS) or trisomy of chromosome 21 (Hsa21) is characterized by impaired hippocampal-dependent learning and memory. These alterations are due to defective neurogenesis and to neuromorphological and functional anomalies of numerous neuronal populations, including hippocampal granular cells (GCs). It has been proposed [...] Read more.
Down syndrome (DS) or trisomy of chromosome 21 (Hsa21) is characterized by impaired hippocampal-dependent learning and memory. These alterations are due to defective neurogenesis and to neuromorphological and functional anomalies of numerous neuronal populations, including hippocampal granular cells (GCs). It has been proposed that the additional gene dose in trisomic cells induces modifications in nuclear compartments and on the chromatin landscape, which could contribute to some DS phenotypes. The Ts65Dn (TS) mouse model of DS carries a triplication of 92 genes orthologous to those found in Hsa21, and shares many phenotypes with DS individuals, including cognitive and neuromorphological alterations. Considering its essential role in hippocampal memory formation, we investigated whether the triplication of this set of Hsa21 orthologous genes in TS mice modifies the nuclear architecture of their GCs. Our results show that the TS mouse presents alterations in the nuclear architecture of its GCs, affecting nuclear compartments involved in transcription and pre-rRNA and pre-mRNA processing. In particular, the GCs of the TS mouse show alterations in the nucleolar fusion pattern and the molecular assembly of Cajal bodies (CBs). Furthermore, hippocampal GCs of TS mice present an epigenetic dysregulation of chromatin that results in an increased heterochromatinization and reduced global transcriptional activity. These nuclear alterations could play an important role in the neuromorphological and/or functional alterations of the hippocampal GCs implicated in the cognitive dysfunction characteristic of TS mice. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Neurodegeneration Disease)
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Review

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16 pages, 770 KiB  
Review
DNA Methylation in Huntington’s Disease
by Nóra Zsindely, Fruzsina Siági and László Bodai
Int. J. Mol. Sci. 2021, 22(23), 12736; https://doi.org/10.3390/ijms222312736 - 25 Nov 2021
Cited by 17 | Viewed by 4277
Abstract
Methylation of cytosine in CpG dinucleotides is the major DNA modification in mammalian cells that is a key component of stable epigenetic marks. This modification, which on the one hand is reversible, while on the other hand, can be maintained through successive rounds [...] Read more.
Methylation of cytosine in CpG dinucleotides is the major DNA modification in mammalian cells that is a key component of stable epigenetic marks. This modification, which on the one hand is reversible, while on the other hand, can be maintained through successive rounds of replication plays roles in gene regulation, genome maintenance, transgenerational epigenetic inheritance, and imprinting. Disturbed DNA methylation contributes to a wide array of human diseases from single-gene disorders to sporadic metabolic diseases or cancer. DNA methylation was also shown to affect several neurodegenerative disorders, including Huntington’s disease (HD), a fatal, monogenic inherited disease. HD is caused by a polyglutamine repeat expansion in the Huntingtin protein that brings about a multifaceted pathogenesis affecting several cellular processes. Research of the last decade found complex, genome-wide DNA methylation changes in HD pathogenesis that modulate transcriptional activity and genome stability. This article reviews current evidence that sheds light on the role of DNA methylation in HD. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Neurodegeneration Disease)
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28 pages, 1505 KiB  
Review
Histone Methylation Regulation in Neurodegenerative Disorders
by Balapal S. Basavarajappa and Shivakumar Subbanna
Int. J. Mol. Sci. 2021, 22(9), 4654; https://doi.org/10.3390/ijms22094654 - 28 Apr 2021
Cited by 49 | Viewed by 7189
Abstract
Advances achieved with molecular biology and genomics technologies have permitted investigators to discover epigenetic mechanisms, such as DNA methylation and histone posttranslational modifications, which are critical for gene expression in almost all tissues and in brain health and disease. These advances have influenced [...] Read more.
Advances achieved with molecular biology and genomics technologies have permitted investigators to discover epigenetic mechanisms, such as DNA methylation and histone posttranslational modifications, which are critical for gene expression in almost all tissues and in brain health and disease. These advances have influenced much interest in understanding the dysregulation of epigenetic mechanisms in neurodegenerative disorders. Although these disorders diverge in their fundamental causes and pathophysiology, several involve the dysregulation of histone methylation-mediated gene expression. Interestingly, epigenetic remodeling via histone methylation in specific brain regions has been suggested to play a critical function in the neurobiology of psychiatric disorders, including that related to neurodegenerative diseases. Prominently, epigenetic dysregulation currently brings considerable interest as an essential player in neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS) and drugs of abuse, including alcohol abuse disorder, where it may facilitate connections between genetic and environmental risk factors or directly influence disease-specific pathological factors. We have discussed the current state of histone methylation, therapeutic strategies, and future perspectives for these disorders. While not somatically heritable, the enzymes responsible for histone methylation regulation, such as histone methyltransferases and demethylases in neurons, are dynamic and reversible. They have become promising potential therapeutic targets to treat or prevent several neurodegenerative disorders. These findings, along with clinical data, may provide links between molecular-level changes and behavioral differences and provide novel avenues through which the epigenome may be targeted early on in people at risk for neurodegenerative disorders. Full article
(This article belongs to the Special Issue Epigenetic Regulation in Neurodegeneration Disease)
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