In ataxia‐teleangiectasia betamethasone response is inversely correlated to cerebellar atrophy and directly to antioxidative capacity

Russo, Ilaria; Cosentino, Claudia; Giudice, Ennio Del; Broccoletti, Teresa; Amorosi, Stefania; Cirillo, Emilia; Aloj, Giuseppina; Fusco, Anna; Costanzo, Vincenzo; Pignata, Claudio

doi:10.1111/j.1468-1331.2009.02600.x

Cited by 45 publications

(38 citation statements)

References 19 publications

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“…ATM-deficient human or mouse cells have increased levels of endogenous ROS and accumulate oxidative damage [18][19][20][21]. H 2 O 2 treatment activates ATM both in vitro and in vivo [25], and ATM is indispensable for protection from ROS accumulation through the G6PD/NAPDH-dependent pathway [24].…”

Section: Discussionmentioning

confidence: 99%

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Increased oxidative stress in AOA3 cells disturbs ATM-dependent DNA damage responses

Kobayashi

Saito

Okui

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Ataxia telangiectasia (AT) is caused by a mutation in the ataxia-telangiectasia-mutated (ATM) gene; the condition is associated with hyper-radiosensitivity, abnormal cell-cycle checkpoints, and genomic instability. AT patients also show cerebellar ataxia, possibly due to reactive oxygen species (ROS) sensitivity in neural cells. The ATM protein is a key regulator of the DNA damage response. Recently, several AT-like disorders have been reported. The genes responsible for them are predicted to encode proteins that interact with ATM in the DNA-damage response. Ataxia with oculomotor apraxia types 1-3 (AOA1, 2, and 3) result in a neurodegenerative and cellular phenotype similar to AT; however, the basis of this phenotypic similarity is unclear. Here, we show that the cells of AOA3 patients display aberrant ATM-dependent phosphorylation and apoptosis following γ-irradiation. The ATM-dependent response to H2O2 treatment was abrogated in AOA3 cells. Furthermore, AOA3 cells had reduced ATM activity. Our results suggest that the attenuated ATM-related response is caused by an increase in endogenous ROS in AOA3 cells. Pretreatment of cells with pyocyanin, which induces endogenous ROS production, abolished the ATM-dependent response. Moreover, AOA3 cells had decreased homologous recombination (HR) activity, and pyocyanin pretreatment reduced HR activity in HeLa cells. These results indicate that excess endogenous ROS represses the ATM-dependent cellular response and HR repair in AOA3 cells. Since the ATM-dependent cell-cycle checkpoint is an important block to carcinogenesis, such inactivation of ATM may lead to tumorigenesis as well as neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

“…AT patients [18,19] and Atm knockout mice show high levels of oxidative damage [20,21]. These data suggest that the impaired response to ROS in AT cells influences neuronal survival.…”

Section: Introductionmentioning

confidence: 99%

Increased oxidative stress in AOA3 cells disturbs ATM-dependent DNA damage responses

Kobayashi

Saito

Okui

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…When ATM is absent the level of ROS is increased and at least in vitro , treatment with antioxidants can increase the survival of Purkinje cells that does not express ATM(Biton et al, 2008). Reducing the ROS level by increasing the antioxidative capacity can reduce cerebellar atrophy in AT patients (Russo et al, 2009). In fact, very recent data shows that conditions of oxidative stress directly oxidize and activate ATM by the formation of disulfide-crosslinked ATM dimers in the absence of DSBs and the MRN complex (Guo et al, 2010).…”

Section: Double-strand Break Repair Deficiencymentioning

confidence: 99%

DNA repair deficiency in neurodegeneration

Jeppesen

Bohr

Stevnsner

2011

Progress in Neurobiology

301

268

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Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington’s disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.

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“…Metabolic syndrome is a broad umbrella term that encompasses a number of chronic disease-associated risk factors, including high blood sugar (diabetes), blood pressure (hypertension), triglycerides, and abdominal fat (obesity), all of which contribute to systemic chronic inflammation. Epidemiological evidence suggests that metabolic syndrome is associated with increased risk of cancers at multi-sites, but it may be gender and age related (120,127). Unlike epidemiological approaches to determine the increased risk of developing renal cancer in those who have metabolic syndrome, we will discuss the putative contribution of metabolic syndrome in the underlying development of renal cancer.…”

Section: Inter-tumor Mediators (Metabolic Syndrome) and Renal Cancer:mentioning

confidence: 99%

Renal Carcinogenesis, Tumor Heterogeneity, and Reactive Oxygen Species: Tactics Evolved

Shanmugasundaram

Block

2016

Antioxidants & Redox Signaling

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Significance: The number of kidney cancers is growing 3-5% each year due to unknown etiologies. Intra-and inter-tumor mediators increase oxidative stress and drive tumor heterogeneity. Recent Advances: Technology advancement in state-of-the-art instrumentation and methodologies allows researchers to detect and characterize global landscaping modifications in genes, proteins, and pathophysiology patterns at the single-cell level. Critical Issues: We postulate that the sources of reactive oxygen species (ROS) and their activation within subcellular compartments will change over a timeline of tumor evolvement and contribute to tumor heterogeneity. Therefore, the complexity of intracellular changes within a tumor and ROS-induced tumor heterogeneity coupled to the advancement of detecting these events globally are limited at the level of data collection, organization, and interpretation using software algorithms and bioinformatics. Future Directions: Integrative and collaborative research, combining the power of numbers with careful experimental design, protocol development, and data interpretation, will translate cancer biology and therapeutics to a heightened level or leave the abundant raw data as stagnant and underutilized. Antioxid. Redox Signal. 25, 685-701.

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In ataxia‐teleangiectasia betamethasone response is inversely correlated to cerebellar atrophy and directly to antioxidative capacity

Abstract: We suggest that antioxidative mechanisms play a role in favouring the improvement of cerebellar functions observed in A-T patients receiving a short-term betamethasone trial.

Cited by 45 publications

References 19 publications

Increased oxidative stress in AOA3 cells disturbs ATM-dependent DNA damage responses

Increased oxidative stress in AOA3 cells disturbs ATM-dependent DNA damage responses

DNA repair deficiency in neurodegeneration

Renal Carcinogenesis, Tumor Heterogeneity, and Reactive Oxygen Species: Tactics Evolved

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