Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases

Translational Neurodegeneration, Год журнала: 2023, Номер 12(1)

Опубликована: Апрель 14, 2023

Abstract Redox homeostasis refers to the balance between production of reactive oxygen species (ROS) as well nitrogen (RNS), and their elimination by antioxidants. It is linked all important cellular activities oxidative stress a result imbalance pro-oxidants antioxidant species. Oxidative perturbs many activities, including processes that maintain integrity DNA. Nucleic acids are highly therefore particularly susceptible damage. The DNA damage response detects repairs these lesions. Efficient repair essential for maintaining viability, but they decline considerably during aging. deficiencies in increasingly described age-related neurodegenerative diseases, such Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis Huntington’s disease. Furthermore, has long been associated with conditions. Moreover, both redox dysregulation increase significantly aging, which biggest risk factor diseases. However, links dysfunction damage, joint contributions pathophysiology conditions, only just emerging. This review will discuss associations address increasing evidence an major source disorders. Understanding connections may facilitate better understanding disease mechanisms, ultimately lead design therapeutic strategies based on preventing

Язык: Английский

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DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(7), С. 6313 - 6313

Опубликована: Март 28, 2023

Parkinson’s disease (PD) is the second most common neurodegenerative around world; however, its pathogenesis remains unclear so far. Recent advances have shown that DNA damage and repair deficiency play an important role in pathophysiology of PD. There growing evidence suggesting involved propagation cellular PD, leading to neuropathology under different conditions. Here, we reviewed current work on First, outlined causes Second, described potential pathways by which mediates neurotoxicity PD discussed precise mechanisms drive these processes damage. In addition, looked ahead interventions targeting repair. Finally, based status research, key problems need be addressed future research were proposed.

Язык: Английский

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Multifunctional scaffolds for bone repair following age-related biological decline: Promising prospects for smart biomaterial-driven technologies

Biomaterials, Год журнала: 2024, Номер 311, С. 122683 - 122683

Опубликована: Июнь 28, 2024

Язык: Английский

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Genome Instability and DNA Repair in Somatic and Reproductive Aging

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2023, Номер 19(1), С. 261 - 290

Опубликована: Окт. 13, 2023

Genetic material is constantly subjected to genotoxic insults and critically dependent on DNA repair. Genome maintenance mechanisms differ in somatic germ cells as the soma only requires during an individual's lifespan, while germline indefinitely perpetuates its genetic information. lesions are recognized repaired by mechanistically highly diverse repair machineries. The damage response impinges a vast array of homeostatic processes can ultimately result cell fate changes such apoptosis or cellular senescence. causally contributes aging process aging-associated diseases, most prominently cancer. By causing mutations, lead diseases impact evolutionary trajectory species. ensuring tight control could be instructive defining strategies for improved They may provide future interventions maintain health prevent disease aging.

Язык: Английский

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A-T neurodegeneration and DNA damage-induced transcriptional stress

DNA repair, Год журнала: 2024, Номер 135, С. 103647 - 103647

Опубликована: Фев. 15, 2024

Язык: Английский

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Senataxin deficiency disrupts proteostasis through nucleolar ncRNA-driven protein aggregation

The Journal of Cell Biology, Год журнала: 2024, Номер 223(7)

Опубликована: Май 8, 2024

Senataxin is an evolutionarily conserved RNA-DNA helicase involved in DNA repair and transcription termination that associated with human neurodegenerative disorders. Here, we investigated whether loss affects protein homeostasis based on previous work showing R-loop-driven accumulation of damage aggregates cells. We find results the insoluble proteins, including many factors known to be prone aggregation These are located primarily nucleolus promoted by upregulation non-coding RNAs expressed from intergenic spacer region ribosomal DNA. also map sites R-loop cells lacking higher hybrids within DNA, peri-centromeric regions, other but not at annotated protein-coding genes. findings indicate solubility proteome through regulation transcription-dependent lesions nucleus nucleolus.

Язык: Английский

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The role of DNA damage in neural stem cells ageing

Journal of Cellular Physiology, Год журнала: 2024, Номер 239(4)

Опубликована: Янв. 14, 2024

Abstract Neural stem cells (NSCs) are pluripotent with the potential to differentiate into a variety of nerve cells. NSCs susceptible both intracellular and extracellular insults, thus causing DNA damage. Extracellular insults include ultraviolet, ionizing radiation, base analogs, modifiers, alkyl agents others, while factors Reactive oxygen species (ROS) radicals produced by mitochondria, mismatches that occur during replication, deamination bases, loss more. When encountered damage, typically employ three coping strategies: repair, damage tolerance, apoptosis. NSCs, like many other cells, have ability divide, differentiate, repair prevent mutations from being passed down next generation. However, when accumulates over time, it will lead series alterations in metabolism which cause cellular ageing. The ageing exhaustion neural cell serious effects on body, such as neurodegenerative diseases. purpose this review is examine processes leads mechanisms NSCs.

Язык: Английский

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ER-associated degradation ligase HRD1 links ER stress to DNA damage repair by modulating the activity of DNA-PKcs

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(37)

Опубликована: Сен. 3, 2024

Proteostasis and genomic integrity are respectively regulated by the endoplasmic reticulum-associated protein degradation (ERAD) DNA damage repair signaling pathways, with both pathways essential for carcinogenesis drug resistance. How these coordinate each other remains unexplored. We found that ER stress specifically induces DNA-PKcs-regulated nonhomologous end joining (NHEJ) pathway to amend impede cell death. Intriguingly, sustained rapidly decreased activity of DNA-PKcs accumulated, facilitating a switch from adaptation This inactivation was caused increased KU70/KU80 degradation. Unexpectedly, ERAD ligase HRD1 efficiently destabilize classic nuclear HDAC1 in cytoplasm, catalyzing HDAC1's polyubiquitination at lysine 74, late stage stress. By abolishing HDAC1-mediated deacetylation, transmits signals nucleus. The resulting enhanced acetylation provides binding sites E3 TRIM25, promotion proteins. Both vitro vivo cancer models showed genetic or pharmacological inhibition HADC1 sensitizes colon cells inducers, including Food Drug Administration-approved celecoxib. antitumor effects combined approach were also observed patient-derived xenograft models. These findings identify mechanistic link between cytoplasm nucleus, indicating anticancer strategies may be developed induce severe while simultaneously inhibiting KU70/KU80/DNA-PKcs-mediated NHEJ signaling.

Язык: Английский

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ATM-mediated co-chaperone DNAJB11 phosphorylation facilitates α-synuclein folding upon DNA double-stranded breaks

Deleted Journal, Год журнала: 2024, Номер 1(2)

Опубликована: Апрель 1, 2024

Abstract Parkinson's disease (PD) is a prevalent neurodegenerative disorder marked by the pathological accumulation of α-synuclein aggregates in dopaminergic neurons. This dyshomeostasis caused an interplay between aging, genetic and environmental factors. Aging process-related DNA damage impaired repair have recently been observed PD process. However, precise neuronal response to remains largely unknown. Here, we demonstrate that double-strand breaks (DSBs) induce aggregation. Analysis large-scale proteomic analysis ATM ATR substrates identified potential candidate HSP70 folding system responding damage. phosphorylates co-chaperone DNAJB11 at threonine 188 which specifically facilitates delivery misfolded α-synuclein, but not tau or transthyretin protein, upon DSBs. Alteration this impairs neurite outgrowth. Remarkably, phosphorylation correlates with severity transgenic SNCA mutant mice patients. These findings reveal damage-responded mechanism through J-domain co-chaperone, offering therapeutic target for PD.

Язык: Английский

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Parkinson’s disease patients display a DNA damage signature in blood that is predictive of disease progression

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 26, 2024

Abstract Aging is the main risk factor for Parkinson’s disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis Progression Markers Initiative cohort investigate involvement DNA damage in PD. Our findings revealed that patients exhibit disrupted repair pathways and biased suppression longer transcripts, indicating presence age-related, transcription-stalling damage. Notably, this signature was only detected with more severe motor symptom progression over three-year period, suggesting its potential as predictor severity. further validated independent cohorts confirmed increased signs dopamine neurons substantia nigra pars compacta through histopathological brains. study sheds light on an aging-related mechanism pathogenesis identifies markers providing readily applicable diagnostic platform prognosticate progression. One Sentence Summary display blood predictive

Язык: Английский

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