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Genotoxicity in Neurodegenerative Disease and Neuropsychiatric Disorders
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Genotoxicity in Neurodegenerative Disease and Neuropsychiatric 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 (31 May 2024) | Viewed by 8644

Special Issue Editors

Prof. Glen E. Kisby

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Guest Editor
College of Osteopathic Medicine of the Pacific Northwest, Western University of Health Sciences, Pomona, CA, USA
Interests: neurotoxins; DNA damage; DNA repair; neurodegenerative disease; neurodevelopmental disorders
Prof. Peter S. Spencer

E-Mail Website
Guest Editor
1. Department of Neurology, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA
2. Oregon Institute for Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, USA
Interests: neurotoxinology; neurotoxicology; systems biology; human disease
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. David M Wilson III

E-Mail Website
Guest Editor
Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium
Interests: oxidative DNA damage; DNA repair mechanisms; neurodegenerative disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Decades of research have identified genetic and environmental factors that are involved in neurodevelopmental, neurodegenerative, and certain neuropsychiatric disorders. Genomic instability, which can be defined as single-nucleotide changes, insertions/deletions, and gross chromosomal aberrations, is a common feature not only of cancer, but also of certain premature aging and inherited as well as sporadic neurodegenerative (amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease) and psychiatric disorders (bipolar disorder, depression, and schizophrenia). Persistent DNA damage, a driver of genomic instability, typically involves the activation of the DNA damage response (DDR) that ensures genomic and proteomic homeostasis in both dividing brain cells and post-mitotic neurons. Failure to repair or resolve excessive genomic stress can lead to cell death or senescence, end points that contribute to the progressive pathogenesis of neurodegenerative disease and the development of certain psychiatric disorders. Recent clinical, genomic, and other molecular studies have uncovered evidence linking DNA damage and the dysregulation of DDR or DNA repair mechanisms with both neurodegenerative and certain psychiatric disorders.

This Special Issue is dedicated to exploring the emerging evidence for DDR, in aging and following environmental stressors, in both neurodegenerative disease and neuropsychiatric disorders. We welcome submissions, including original papers and reviews, on (i) genotoxin exposures in the development of neurological disorders, (ii) methods to assess DNA damage and repair in neural cell types, including at the genome-wide level, (iii) molecular processes related to genomic stability that preserve CNS homeostasis and functionality, and (iv) the effects of aging on neurological disease risk.

Prof. Glen E. Kisby
Prof. Peter S. Spencer
Prof. Dr. David M Wilson III
Guest Editors

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

  • genomic instability
  • DNA damage
  • DNA damage response (DDR)
  • DNA repair
  • apoptosis
  • cellular senescence
  • aging
  • neurodegeneration
  • psychiatric disorders

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Published Papers (7 papers)

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Research

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25 pages, 10825 KiB  
Article
Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage
by Lee J. Martin, Shannon J. Koh, Antionette Price, Dongseok Park and Byung Woo Kim
Int. J. Mol. Sci. 2024, 25(16), 9106; https://doi.org/10.3390/ijms25169106 - 22 Aug 2024
Viewed by 773
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal disease that causes degeneration of motor neurons (MNs) and paralysis. ALS can be caused by mutations in the gene that encodes copper/zinc superoxide dismutase (SOD1). SOD1 is known mostly as a cytosolic antioxidant protein, but SOD1 [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal disease that causes degeneration of motor neurons (MNs) and paralysis. ALS can be caused by mutations in the gene that encodes copper/zinc superoxide dismutase (SOD1). SOD1 is known mostly as a cytosolic antioxidant protein, but SOD1 is also in the nucleus of non-transgenic (tg) and human SOD1 (hSOD1) tg mouse MNs. SOD1’s nuclear presence in different cell types and subnuclear compartmentations are unknown, as are the nuclear functions of SOD1. We examined hSOD1 nuclear localization and DNA damage in tg mice expressing mutated and wildtype variants of hSOD1 (hSOD1-G93A and hSOD1-wildtype). We also studied ALS patient-derived induced pluripotent stem (iPS) cells to determine the nuclear presence of SOD1 in undifferentiated and differentiated MNs. In hSOD1-G93A and hSOD1-wildtype tg mice, choline acetyltransferase (ChAT)-positive MNs had nuclear hSOD1, but while hSOD1-wildtype mouse MNs also had nuclear ChAT, hSOD1-G93A mouse MNs showed symptom-related loss of nuclear ChAT. The interneurons had preserved parvalbumin nuclear positivity in hSOD1-G93A mice. hSOD1-G93A was seen less commonly in spinal cord astrocytes and, notably, oligodendrocytes, but as the disease emerged, the oligodendrocytes had increased mutant hSOD1 nuclear presence. Brain and spinal cord subcellular fractionation identified mutant hSOD1 in soluble nuclear extracts of the brain and spinal cord, but mutant hSOD1 was concentrated in the chromatin nuclear extract only in the spinal cord. Nuclear extracts from mutant hSOD1 tg mouse spinal cords had altered protein nitration, footprinting peroxynitrite presence, and the intact nuclear extracts had strongly increased superoxide production as well as the active NADPH oxidase marker, p47phox. The comet assay showed that MNs from hSOD1-G93A mice progressively (6–14 weeks of age) accumulated DNA single-strand breaks. Ablation of the NCF1 gene, encoding p47phox, and pharmacological inhibition of NADPH oxidase with systemic treatment of apocynin (10 mg/kg, ip) extended the mean lifespan of hSOD1-G93A mice by about 25% and mitigated genomic DNA damage progression. In human postmortem CNS, SOD1 was found in the nucleus of neurons and glia; nuclear SOD1 was increased in degenerating neurons in ALS cases and formed inclusions. Human iPS cells had nuclear SOD1 during directed differentiation to MNs, but mutant SOD1-expressing cells failed to establish wildtype MN nuclear SOD1 levels. We conclude that SOD1 has a prominent nuclear presence in the central nervous system, perhaps adopting aberrant contexts to participate in ALS pathobiology. Full article
(This article belongs to the Special Issue Genotoxicity in Neurodegenerative Disease and Neuropsychiatric Disorders)
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20 pages, 5818 KiB  
Article
Cell-Type-Dependent Recruitment Dynamics of FUS Protein at Laser-Induced DNA Damage Sites
by Yu Niu, Arun Pal, Barbara Szewczyk, Julia Japtok, Marcel Naumann, Hannes Glaß and Andreas Hermann
Int. J. Mol. Sci. 2024, 25(6), 3526; https://doi.org/10.3390/ijms25063526 - 20 Mar 2024
Cited by 1 | Viewed by 1385
Abstract
Increased signs of DNA damage have been associated to aging and neurodegenerative diseases. DNA damage repair mechanisms are tightly regulated and involve different pathways depending on cell types and proliferative vs. postmitotic states. Amongst them, fused in sarcoma (FUS) was reported to be [...] Read more.
Increased signs of DNA damage have been associated to aging and neurodegenerative diseases. DNA damage repair mechanisms are tightly regulated and involve different pathways depending on cell types and proliferative vs. postmitotic states. Amongst them, fused in sarcoma (FUS) was reported to be involved in different pathways of single- and double-strand break repair, including an early recruitment to DNA damage. FUS is a ubiquitously expressed protein, but if mutated, leads to a more or less selective motor neurodegeneration, causing amyotrophic lateral sclerosis (ALS). Of note, ALS-causing mutation leads to impaired DNA damage repair. We thus asked whether FUS recruitment dynamics differ across different cell types putatively contributing to such cell-type-specific vulnerability. For this, we generated engineered human induced pluripotent stem cells carrying wild-type FUS-eGFP and analyzed different derivatives from these, combining a laser micro-irradiation technique and a workflow to analyze the real-time process of FUS at DNA damage sites. All cells showed FUS recruitment to DNA damage sites except for hiPSC, with only 70% of cells recruiting FUS. In-depth analysis of the kinetics of FUS recruitment at DNA damage sites revealed differences among cellular types in response to laser-irradiation-induced DNA damage. Our work suggests a cell-type-dependent recruitment behavior of FUS during the DNA damage response and repair procedure. The presented workflow might be a valuable tool for studying the proteins recruited at the DNA damage site in a real-time course. Full article
(This article belongs to the Special Issue Genotoxicity in Neurodegenerative Disease and Neuropsychiatric Disorders)
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Review

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8 pages, 508 KiB  
Review
Accidental Encounter of Repair Intermediates in Alkylated DNA May Lead to Double-Strand Breaks in Resting Cells
by Shingo Fujii and Robert P. Fuchs
Int. J. Mol. Sci. 2024, 25(15), 8192; https://doi.org/10.3390/ijms25158192 - 26 Jul 2024
Viewed by 721
Abstract
In clinics, chemotherapy is often combined with surgery and radiation to increase the chances of curing cancers. In the case of glioblastoma (GBM), patients are treated with a combination of radiotherapy and TMZ over several weeks. Despite its common use, the mechanism of [...] Read more.
In clinics, chemotherapy is often combined with surgery and radiation to increase the chances of curing cancers. In the case of glioblastoma (GBM), patients are treated with a combination of radiotherapy and TMZ over several weeks. Despite its common use, the mechanism of action of the alkylating agent TMZ has not been well understood when it comes to its cytotoxic effects in tumor cells that are mostly non-dividing. The cellular response to alkylating DNA damage is operated by an intricate protein network involving multiple DNA repair pathways and numerous checkpoint proteins that are dependent on the type of DNA lesion, the cell type, and the cellular proliferation state. Among the various alkylating damages, researchers have placed a special on O6-methylguanine (O6-mG). Indeed, this lesion is efficiently removed via direct reversal by O6-methylguanine-DNA methyltransferase (MGMT). As the level of MGMT expression was found to be directly correlated with TMZ efficiency, O6-mG was identified as the critical lesion for TMZ mode of action. Initially, the mode of action of TMZ was proposed as follows: when left on the genome, O6-mG lesions form O6-mG: T mispairs during replication as T is preferentially mis-inserted across O6-mG. These O6-mG: T mispairs are recognized and tentatively repaired by a post-replicative mismatched DNA correction system (i.e., the MMR system). There are two models (futile cycle and direct signaling models) to account for the cytotoxic effects of the O6-mG lesions, both depending upon the functional MMR system in replicating cells. Alternatively, to explain the cytotoxic effects of alkylating agents in non-replicating cells, we have proposed a “repair accident model” whose molecular mechanism is dependent upon crosstalk between the MMR and the base excision repair (BER) systems. The accidental encounter between these two repair systems will cause the formation of cytotoxic DNA double-strand breaks (DSBs). In this review, we summarize these non-exclusive models to explain the cytotoxic effects of alkylating agents and discuss potential strategies to improve the clinical use of alkylating agents. Full article
(This article belongs to the Special Issue Genotoxicity in Neurodegenerative Disease and Neuropsychiatric Disorders)
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12 pages, 1213 KiB  
Review
Tau beyond Tangles: DNA Damage Response and Cytoskeletal Protein Crosstalk on Neurodegeneration
by Megumi Asada-Utsugi and Makoto Urushitani
Int. J. Mol. Sci. 2024, 25(14), 7906; https://doi.org/10.3390/ijms25147906 - 19 Jul 2024
Viewed by 963
Abstract
Neurons in the brain are continuously exposed to various sources of DNA damage. Although the mechanisms of DNA damage repair in mitotic cells have been extensively characterized, the repair pathways in post-mitotic neurons are still largely elusive. Moreover, inaccurate repair can result in [...] Read more.
Neurons in the brain are continuously exposed to various sources of DNA damage. Although the mechanisms of DNA damage repair in mitotic cells have been extensively characterized, the repair pathways in post-mitotic neurons are still largely elusive. Moreover, inaccurate repair can result in deleterious mutations, including deletions, insertions, and chromosomal translocations, ultimately compromising genomic stability. Since neurons are terminally differentiated cells, they cannot employ homologous recombination (HR) for double-strand break (DSB) repair, suggesting the existence of neuron-specific repair mechanisms. Our research has centered on the microtubule-associated protein tau (MAPT), a crucial pathological protein implicated in neurodegenerative diseases, and its interplay with neurons’ DNA damage response (DDR). This review aims to provide an updated synthesis of the current understanding of the complex interplay between DDR and cytoskeletal proteins in neurons, with a particular focus on the role of tau in neurodegenerative disorders. Full article
(This article belongs to the Special Issue Genotoxicity in Neurodegenerative Disease and Neuropsychiatric Disorders)
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12 pages, 482 KiB  
Review
Adaptive and Maladaptive DNA Breaks in Neuronal Physiology and Alzheimer’s Disease
by Anysja Roberts, Russell H. Swerdlow and Ning Wang
Int. J. Mol. Sci. 2024, 25(14), 7774; https://doi.org/10.3390/ijms25147774 - 16 Jul 2024
Viewed by 778
Abstract
DNA strand breaks excessively accumulate in the brains of patients with Alzheimer’s disease (AD). While traditionally considered random, deleterious events, neuron activity itself induces DNA breaks, and these “adaptive” breaks help mediate synaptic plasticity and memory formation. Recent studies mapping the brain DNA [...] Read more.
DNA strand breaks excessively accumulate in the brains of patients with Alzheimer’s disease (AD). While traditionally considered random, deleterious events, neuron activity itself induces DNA breaks, and these “adaptive” breaks help mediate synaptic plasticity and memory formation. Recent studies mapping the brain DNA break landscape reveal that despite a net increase in DNA breaks in ectopic genomic hotspots, adaptive DNA breaks around synaptic genes are lost in AD brains, and this is associated with transcriptomic dysregulation. Additionally, relationships exist between mitochondrial dysfunction, a hallmark of AD, and DNA damage, such that mitochondrial dysfunction may perturb adaptive DNA break formation, while DNA breaks may conversely impair mitochondrial function. A failure of DNA break physiology could, therefore, potentially contribute to AD pathogenesis. Full article
(This article belongs to the Special Issue Genotoxicity in Neurodegenerative Disease and Neuropsychiatric Disorders)
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21 pages, 1097 KiB  
Review
Introducing the Role of Genotoxicity in Neurodegenerative Diseases and Neuropsychiatric Disorders
by Glen E. Kisby, David M. Wilson III and Peter S. Spencer
Int. J. Mol. Sci. 2024, 25(13), 7221; https://doi.org/10.3390/ijms25137221 - 29 Jun 2024
Cited by 1 | Viewed by 1430
Abstract
Decades of research have identified genetic and environmental factors involved in age-related neurodegenerative diseases and, to a lesser extent, neuropsychiatric disorders. Genomic instability, i.e., the loss of genome integrity, is a common feature among both neurodegenerative (mayo-trophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease) [...] Read more.
Decades of research have identified genetic and environmental factors involved in age-related neurodegenerative diseases and, to a lesser extent, neuropsychiatric disorders. Genomic instability, i.e., the loss of genome integrity, is a common feature among both neurodegenerative (mayo-trophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease) and psychiatric (schizophrenia, autism, bipolar depression) disorders. Genomic instability is associated with the accumulation of persistent DNA damage and the activation of DNA damage response (DDR) pathways, as well as pathologic neuronal cell loss or senescence. Typically, DDR signaling ensures that genomic and proteomic homeostasis are maintained in both dividing cells, including neural progenitors, and post-mitotic neurons. However, dysregulation of these protective responses, in part due to aging or environmental insults, contributes to the progressive development of neurodegenerative and/or psychiatric disorders. In this Special Issue, we introduce and highlight the overlap between neurodegenerative diseases and neuropsychiatric disorders, as well as the emerging clinical, genomic, and molecular evidence for the contributions of DNA damage and aberrant DNA repair. Our goal is to illuminate the importance of this subject to uncover possible treatment and prevention strategies for relevant devastating brain diseases. Full article
(This article belongs to the Special Issue Genotoxicity in Neurodegenerative Disease and Neuropsychiatric Disorders)
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Other

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20 pages, 3994 KiB  
Perspective
Novel Techniques for Mapping DNA Damage and Repair in the Brain
by Jenna Hedlich-Dwyer, Joanne S. Allard, Veronica E. Mulgrave, Glen E. Kisby, Jacob Raber and Natalie R. Gassman
Int. J. Mol. Sci. 2024, 25(13), 7021; https://doi.org/10.3390/ijms25137021 - 27 Jun 2024
Viewed by 1640
Abstract
DNA damage in the brain is influenced by endogenous processes and metabolism along with exogenous exposures. Accumulation of DNA damage in the brain can contribute to various neurological disorders, including neurodegenerative diseases and neuropsychiatric disorders. Traditional methods for assessing DNA damage in the [...] Read more.
DNA damage in the brain is influenced by endogenous processes and metabolism along with exogenous exposures. Accumulation of DNA damage in the brain can contribute to various neurological disorders, including neurodegenerative diseases and neuropsychiatric disorders. Traditional methods for assessing DNA damage in the brain, such as immunohistochemistry and mass spectrometry, have provided valuable insights but are limited by their inability to map specific DNA adducts and regional distributions within the brain or genome. Recent advancements in DNA damage detection methods offer new opportunities to address these limitations and further our understanding of DNA damage and repair in the brain. Here, we review emerging techniques offering more precise and sensitive ways to detect and quantify DNA lesions in the brain or neural cells. We highlight the advancements and applications of these techniques and discuss their potential for determining the role of DNA damage in neurological disease. Full article
(This article belongs to the Special Issue Genotoxicity in Neurodegenerative Disease and Neuropsychiatric Disorders)
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