Persistent DNA damage alters the neuronal transcriptome suggesting cell cycle dysregulation and altered mitochondrial function

Vázquez-Villaseñor, Irina; Garwood, Claire J.; Simpson, Julie E.; Heath, Paul R.; Mortiboys, Heather; Wharton, Stephen B.

doi:10.1111/ejn.15466

Cited by 10 publications

(6 citation statements)

References 62 publications

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“…If our prediction is correct, persistent repair intermediates will likely trigger neuronal senescence through a sustained ATR signaling axis. While the direct evidence related to this hypothesis currently lacks, transcriptome profiling of neurons characterized with persistent DDR did reveal an induction of gene expression patterns mapped to the ATR-dependent DDR and APC/C cycle regulatory complex and p53 signaling [247] (Fig. 2).…”

Section: Permanent Cell Cycle Arrest Following Cell Cycle Re-entry In...mentioning

confidence: 99%

DNA Damage Response-Associated Cell Cycle Re-Entry and Neuronal Senescence in Brain Aging and Alzheimer’s Disease

Wong

Chow

2023

JAD

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Chronological aging is by far the strongest risk factor for age-related dementia and Alzheimer’s disease. Senescent cells accumulated in the aging and Alzheimer’s disease brains are now recognized as the keys to describing such an association. Cellular senescence is a classic phenomenon characterized by stable cell arrest, which is thought to be applicable only to dividing cells. Emerging evidence indicates that fully differentiated post-mitotic neurons are also capable of becoming senescent, with roles in contributing to both brain aging and disease pathogenesis. The key question that arises is the identity of the upstream triggers and the molecular mechanisms that underly such changes. Here, we highlight the potential role of persistent DNA damage response as the major driver of senescent phenotypes and discuss the current evidence and molecular mechanisms that connect DNA repair infidelity, cell cycle re-entry and terminal fate decision in committing neuronal cell senescence.

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Section: Permanent Cell Cycle Arrest Following Cell Cycle Re-entry In...mentioning

confidence: 99%

DNA Damage Response-Associated Cell Cycle Re-Entry and Neuronal Senescence in Brain Aging and Alzheimer’s Disease

Wong

Chow

2023

JAD

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“…In the literature various in vitro cell culture models were created using hydrogen peroxide. Sameti et al investigated the effect of hydrogen peroxide on bioenergetic mechanism in astrocytes and LUHMES cell line [34]; in another study, they investigated the effect of hydrogen peroxide directly on DNA damage [35]. Schlachetzki et al examined the effects of hydrogen peroxide on neurodegenerative diseases in cell culture models [36].…”

Section: Discussionmentioning

confidence: 99%

Establishing an Oxidative Stress Model in the Human Mesencephalic Cell Line (LUHMES): an in vitro study

Sevim Akan,

Örsoğlu,

Gurpinar

2024

Hacettepe Journal of Biology and Chemistry

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Oxidative stress-caused neurodegenerative diseases, such as Alzheimer's, Parkinson's disease, and amyotrophic lateral sclerosis, are widely recognized as the most prevalent brain and central nervous system disorders. This is attributed to the vulnerability of neurons to oxidative stress within the body. Although substantial research has been performed on these diseases, it is extremely difficult to establish an oxidative stress model for brain tissues. In primary cultures, it is difficult to obtain neurons and the continuity of the culture is limited for in vitro cell line models. By providing valuable insights into the mechanisms of oxidative stress-induced neurodegenerative diseases, these in vitro models can aid in the development of effective treatment strategies. Here, we developed an in vitro oxidative stress model utilizing hydrogen peroxide on the LUHMES cell line. Our study evaluated the impact of this model on LUHMES cell viability and the equilibrium between oxidants and antioxidants by assaying total oxidant capacity (TOC) and total antioxidant capacity (TAC). Our results provided evidence of the oxidative effect of hydrogen peroxide in critical concentration and proved the efficacy of this model for further investigations.

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“…Oxidative-stress-induced DNA damage can also induce changes in the neuronal cell cycle to activate a persistent DNA damage response, leading to neuronal senescence [ 56 ]. SHS exposure increased the levels of p21-labeled cells in the prefrontal cortex and hippocampus, but not β-galactosidase activity, a widely used marker of cellular senescence that is also elevated in neurons with high energetic and metabolic demands [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Behavioral and Cognitive Performance Following Exposure to Second-Hand Smoke (SHS) from Tobacco Products Associated with Oxidative-Stress-Induced DNA Damage and Repair and Disruption of the Gut Microbiome

Raber,

Stagaman,

Kasschau

et al. 2023

Genes

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Exposure to second-hand Smoke (SHS) remains prevalent. The underlying mechanisms of how SHS affects the brain require elucidation. We tested the hypothesis that SHS inhalation drives changes in the gut microbiome, impacting behavioral and cognitive performance as well as neuropathology in two-month-old wild-type (WT) mice and mice expressing wild-type human tau, a genetic model pertinent to Alzheimer’s disease mice, following chronic SHS exposure (10 months to ~30 mg/m3). SHS exposure impacted the composition of the gut microbiome as well as the biodiversity and evenness of the gut microbiome in a sex-dependent fashion. This variation in the composition and biodiversity of the gut microbiome is also associated with several measures of cognitive performance. These results support the hypothesis that the gut microbiome contributes to the effect of SHS exposure on cognition. The percentage of 8-OHdG-labeled cells in the CA1 region of the hippocampus was also associated with performance in the novel object recognition test, consistent with urine and serum levels of 8-OHdG serving as a biomarker of cognitive performance in humans. We also assessed the effects of SHS on the percentage of p21-labeled cells, an early cellular marker of senescence that is upregulated in bronchial cells after exposure to cigarette smoke. Nuclear staining of p21-labeled cells was more prominent in larger cells of the prefrontal cortex and CA1 hippocampal neurons of SHS-exposed mice than in sham-exposed mice, and there was a significantly greater percentage of labelled cells in the prefrontal cortex and CA1 region of the hippocampus of SHS than air-exposed mice, suggesting that exposure to SHS may result in accelerated brain aging through oxidative-stress-induced injury.

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Persistent DNA damage alters the neuronal transcriptome suggesting cell cycle dysregulation and altered mitochondrial function

Cited by 10 publications

References 62 publications

DNA Damage Response-Associated Cell Cycle Re-Entry and Neuronal Senescence in Brain Aging and Alzheimer’s Disease

DNA Damage Response-Associated Cell Cycle Re-Entry and Neuronal Senescence in Brain Aging and Alzheimer’s Disease

Establishing an Oxidative Stress Model in the Human Mesencephalic Cell Line (LUHMES): an in vitro study

Behavioral and Cognitive Performance Following Exposure to Second-Hand Smoke (SHS) from Tobacco Products Associated with Oxidative-Stress-Induced DNA Damage and Repair and Disruption of the Gut Microbiome

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