Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Gupta, Swapnil; You, Panpan; SenGupta, Tanima; Nilsen, Hilde; Sharma, Kusum

doi:10.3390/biology10020163

Cited by 15 publications

(13 citation statements)

References 216 publications

(151 reference statements)

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“…Oxidative stress is also considered as a cause of neurodegenerative diseases. 15,16) Our results suggest that oxidative stress leads to the development of neurodegenerative diseases by a mechanism of endocytosis inhibition that is different from the previously reported ROS-mediated damage to DNA, proteins, lipids, and organelles. [15][16][17] Our findings show that decreased VAMP8 transport to lysosomes inhibits autophagy (Fig.…”

Section: Discussioncontrasting

confidence: 95%

“…15) Oxidative stress is caused by an increase in intracellular reactive oxygen species (ROS). Although ROS has been implicated in the development of neurodegenerative diseases by causing neuronal cell death via DNA, proteins, lipids, or organelle damage, 16,17) it is unclear whether oxidative stress is involved in the accumulation of proteins responsible for neurodegenerative diseases. Furthermore, it has been reported that oxidative stress also attenuates endocytosis.…”

Section: Introductionmentioning

confidence: 99%

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Oxidative Stress Impairs Autophagy <i>via</i> Inhibition of Lysosomal Transport of VAMP8

Ohnishi

Tsuji

Itoh

2022

Biological & Pharmaceutical Bulletin

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Autophagy is a highly conserved intracellular degrading system and its dysfunction is considered related to the cause of neurodegenerative disorders. A previous study showed that the inhibition of endocytosis transport attenuates soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein transport to lysosomes and block autophagy. The other studies demonstrated oxidative stress, one of the inducers of neurodegenerative diseases inhibits endocytosis transport. Thus, we hypothesized that oxidative stress-induced endocytosis inhibition causes alteration of SNARE protein transport to lysosomes and impairs autophagy. Here, we demonstrated that oxidative stress inhibits endocytosis and decreased the lysosomal localization of VAMP8, one of the autophagy-related SNARE proteins in a human neuroblastoma cell line. Moreover, this oxidative stress induction blocked the autophagosome-lysosome fusion step. Since we also observed decreased lysosomal localization of VAMP8 and inhibition of autophagosome-lysosome fusion in endocytosis inhibitor-treated cells, oxidative stress may inhibit VAMP8 trafficking by suppressing endocytosis and impair autophagy. Our findings suggest that oxidative stress-induced inhibition of VAMP8 trafficking to lysosomes is associated with the development of neurodegenerative diseases due to the blocked autophagosome-lysosome fusion, and may provide a new therapeutic target for restoring the autophagic activity.

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Section: Discussioncontrasting

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Oxidative Stress Impairs Autophagy <i>via</i> Inhibition of Lysosomal Transport of VAMP8

Ohnishi

Tsuji

Itoh

2022

Biological & Pharmaceutical Bulletin

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“…Recent studies show that the DNA damage induced by genotoxins in post-mitotic neurons maps to hotspots of DNA repair across the genome ( Reid et al, 2021 ; Wu et al, 2021 ), with repair sites predominantly located in neuronal enhancers at sites of CpG DNA methylation ( Wu et al, 2021 ). Such mechanisms may explain the elevated levels of DNA damage and epigenetic changes that occur in the prefrontal cortex of the MAM animal model of schizophrenia ( Maćkowiak et al, 2014 ; Perez et al, 2016 ; Gulchina et al, 2017 ; Steullet et al, 2017 ) and the neurodegenerative phenotype that develops in inherited DNA-repair disorders ( Tiwari and Wilson, 2019 ; Ainslie et al, 2021 ; Gupta et al, 2021 ).…”

Section: Genomic Instability and Cycad Toxinsmentioning

confidence: 99%

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Kisby

Spencer

2021

Front. Neurosci.

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Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) is a disappearing prototypical neurodegenerative disorder (tau-dominated polyproteinopathy) linked with prior exposure to phytogenotoxins in cycad seed used for medicine and/or food. The principal cycad genotoxin, methylazoxymethanol (MAM), forms reactive carbon-centered ions that alkylate nucleic acids in fetal rodent brain and, depending on the timing of systemic administration, induces persistent developmental abnormalities of the cortex, hippocampus, cerebellum, and retina. Whereas administration of MAM prenatally or postnatally can produce animal models of epilepsy, schizophrenia or ataxia, administration to adult animals produces little effect on brain structure or function. The neurotoxic effects of MAM administered to rats during cortical brain development (specifically, gestation day 17) are used to model the histological, neurophysiological and behavioral deficits of human schizophrenia, a condition that may precede or follow clinical onset of motor neuron disease in subjects with sporadic ALS and ALS/PDC. While studies of migrants to and from communities impacted by ALS/PDC indicate the degenerative brain disorder may be acquired in juvenile and adult life, a proportion of indigenous cases shows neurodevelopmental aberrations in the cerebellum and retina consistent with MAM exposure in utero. MAM induces specific patterns of DNA damage and repair that associate with increased tau expression in primary rat neuronal cultures and with brain transcriptional changes that parallel those associated with human ALS and Alzheimer’s disease. We examine MAM in relation to neurodevelopment, epigenetic modification, DNA damage/replicative stress, genomic instability, somatic mutation, cell-cycle reentry and cellular senescence. Since the majority of neurodegenerative disease lacks a solely inherited genetic basis, research is needed to explore the hypothesis that early-life exposure to genotoxic agents may trigger or promote molecular events that culminate in neurodegeneration.

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“…Additionally, the worm has a rapid life cycle and short generation time which will allow high throughput testing (Corsi et al 2015;Nigon and Félix 2017). Most of the pathways involved in genomic integrity that are known through studies of bacteria, yeast, mammals, and human cell lines are also highly conserved in C. elegans, which makes the worm an experimental model greatly suited for research on processes involved in genomic stability (Elsakrmy et al 2020;Gupta et al 2021).…”

Section: Advantages Of the Model Organism And Alkaline Unwinding Compared To Other Genotoxicity Testsmentioning

confidence: 99%

A fast and reliable method for monitoring genomic instability in the model organism Caenorhabditis elegans

et al. 2021

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The identification of genotoxic agents and their potential for genotoxic alterations in an organism is crucial for risk assessment and approval procedures of the chemical and pharmaceutical industry. Classically, testing strategies for DNA or chromosomal damage focus on in vitro and in vivo (mainly rodent) investigations. In cell culture systems, the alkaline unwinding (AU) assay is one of the well-established methods for detecting the percentage of double-stranded DNA (dsDNA). By establishing a reliable lysis protocol, and further optimization of the AU assay for the model organism Caenorhabditis elegans (C. elegans), we provided a new tool for genotoxicity testing in the niche between in vitro and rodent experiments. The method is intended to complement existing testing strategies by a multicellular organism, which allows higher predictability of genotoxic potential compared to in vitro cell line or bacterial investigations, before utilizing in vivo (rodent) investigations. This also allows working within the 3R concept (reduction, refinement, and replacement of animal experiments), by reducing and possibly replacing animal testing. Validation with known genotoxic agents (bleomycin (BLM) and tert-butyl hydroperoxide (tBOOH)) proved the method to be meaningful, reproducible, and feasible for high-throughput genotoxicity testing, and especially preliminary screening.

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Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Cited by 15 publications

References 216 publications

Oxidative Stress Impairs Autophagy <i>via</i> Inhibition of Lysosomal Transport of VAMP8

Oxidative Stress Impairs Autophagy <i>via</i> Inhibition of Lysosomal Transport of VAMP8

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

A fast and reliable method for monitoring genomic instability in the model organism Caenorhabditis elegans

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