Inflammation, a significant player of Ataxia–Telangiectasia pathogenesis?

Zaki‐Dizaji, Majid; Akrami, Seyed Mohammad; Azizi, Gholamreza; Abolhassani, Hassan; Aghamohammadi, Asghar

doi:10.1007/s00011-018-1142-y

Cited by 39 publications

(28 citation statements)

References 155 publications

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“…They manifest radiosensitivity, sterility, and immunodeficiencies with an elevated risk of developing autoimmune diseases such as arthritis, vitiligo, or immune thrombocytopenia [104]. Authors have also suggested that A-T patients may suffer from prolonged chronic inflammation [94]. Consistent with this, high levels of pro-inflammation cytokines are present in their serum even in the absence of infections [51,52].…”

Section: Molecular Basis For Ataxia Telangiectasia Syndromementioning

confidence: 93%

“…While the complex relationships between DDR and inflammation are beginning to emerge, it is clear that ROS and other types of genomic injuries can elicit a proinflammatory response. As part of DDR, this pro-survival cell response is mediated mostly through ATM and PARP1 [94]. ATM directly binds and phosphorylates IKK-γ (NEMO), the regulatory subunit of the IKK complex that activates NF-kB [41].…”

Section: Other Ddr Pathwaysmentioning

confidence: 99%

“…Along with PARP1-mediated post-translational modifications, ATM phosphorylation of IKK-γ promotes activation of IKK and subsequent activation of NF-kB [41,[95][96][97]. Therefore, this critical pro-inflammatory enzyme is under DDR control, where it can function as a transcription factor promoting expression of pro-inflammatory cytokines and DNA repair genes [76, 94,95,98]. In addition, ATM is involved in a pro-inflammatory pathway known as senescence-associated secretory phenotype (SASP), a complex mechanism that secretes, among others, pro-inflammatory cytokines [94,99].…”

Section: Other Ddr Pathwaysmentioning

confidence: 99%

“…The cause for this phenotype is likely to be multifactorial, but it is well-defined that ATM phosphorylates several targets-e.g., translation regulation 4E-BP1-in response to insulin [25]. Furthermore, a lack of fully functional ATM correlates with an inhibition of IRS1 (insulin receptor substrate 1) and low levels of IGF1-R (insulin-like growth factor1 receptor), suggesting possible mechanisms causing this clinical feature [94,136,137].…”

Section: Other Clinical Featuresmentioning

confidence: 99%

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The Role of the DNA Damage Response in Ataxia-Telangiectasia Syndrome

Ribes-Zamora¹

2019

Neurodevelopment and Neurodevelopmental Disease [Working Title]

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The DNA damage response (DDR) is a concerted response involving a myriad of pathways that cells elicit in the presence of DNA injuries. Patients bearing mutations in DDR genes have an increased cancer incidence derived from their diminished ability to respond to DNA damage, and the consequent increase in mutations. Intriguingly, mutations in ATM, the chief DDR regulator, can cause ataxia telangiectasia, a neurodegenerative disorder characterized by progressive loss of movement coordination, weak immune system, and increased cancer risk. The relationship between ATM and neural system development and degeneration remains to be fully elucidated and will be discussed in this chapter. Neurodevelopment and Neurodevelopmental Disorder 2Somewhat surprisingly, mutations in genes belonging to DDR pathways correlate with neurodevelopmental defects and neurodegenerative pathologies [5,[9][10][11]. For instance, individuals with dysfunctional versions of SSB repair genes APTX, PNPK, or XRCC1 manifest different types of ataxias with ocular apraxia; whereas, defective TDP1, also involved in SSB repair, can cause spinocerebellar ataxia with axonal neuropathy [9, 12]. Similarly, mutations in DSB repair gene MRE11, or central DDR regulators ATM and ATR, can lead to cerebellar ataxia [5, 13]. Besides ataxias, microcephaly is commonly found linked to defects in several DDR associated genes [1, 5, 14]. Mutations in NBS1 and RAD50, two genes involved in end processing during DSB repair, can cause Nijmegen breakage syndrome (NBS) and NBS-like syndrome, respectively, both syndromes manifesting microcephaly among other conditions [5, 15, 16]. Microcephalia is also present in individuals with dysfunctional PNPK, LIG4-a gene involved in DSB repair-or Seckel Syndrome 1, a developmental disorder caused by some ATR mutations [9, 15]. Furthermore, around 25% of patients with defective nucleotide excision repair (NER)-a DDR pathway in charge of healing photoproducts created by UV light exposure-can also present microcephaly among other neurological problems [5]. Overall, this data suggest a strong and intriguing link between DDR, neurodevelopment, and neuropathology. This review focuses on ATM, its role during DDR, and the molecular basis of ataxia-telangiectasia (A-T), a neurodegenerative syndrome caused by defective or absent ATM. ATM roles during DDRATM and ATR are two kinases belonging to the protein phosphatidylinositol-3-kinase-like kinases (PIKK) family that function as the chief regulators of DDR [3, 11, 13]. Together, they coordinate all pathways implicated in DDR to offer an adequate and timely response proportionate to the type and extent of the genomic injury. Recently, DNA-PKcs, another member of the PIKK family, has also been found playing more substantial roles in regulating DDR than initially thought, albeit to a lesser extent that ATM and ATR [17].ATM is a very large kinase of 3056 amino acids and a molecular weight of 350.6 kD that resides in the nucleus as inactive homodimers. Upon DNA damage infliction, phosphorylation of a ...

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Section: Molecular Basis For Ataxia Telangiectasia Syndromementioning

confidence: 93%

Section: Other Ddr Pathwaysmentioning

confidence: 99%

Section: Other Ddr Pathwaysmentioning

confidence: 99%

Section: Other Clinical Featuresmentioning

confidence: 99%

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The Role of the DNA Damage Response in Ataxia-Telangiectasia Syndrome

Ribes-Zamora¹

2019

Neurodevelopment and Neurodevelopmental Disease [Working Title]

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“…A taxia-telangiectasia (a-t) is a rare autosomal recessive pleiotropic syndrome characterised by cerebellar ataxia, oculocutaneous telangiectasia, chromosomal instability, radiosensitivity, variable immunodeficiency, oxidative stress and a high risk of malignancy. 1,2 Worldwide, only one in 40,000-100,000 neonates is homozygous for the A-T mutated (ATM) gene mutation; however, 0.5-2% of the general population are heterozygous carriers. 1 Although heterozygous ATM carriers are commonly asymptomatic, they have a higher sensitivity to ionising radiation (IR) and a higher risk of type 2 diabetes mellitus, cardiovascular diseases and cancers.…”

mentioning

confidence: 99%

Individual Radiosensitivity Assessment of the Families of Ataxia-Telangiectasia Patients by G2-Checkpoint Abrogation

Aghamohammadi

Akrami

Yaghmaie

et al. 2019

Sultan Qaboos Univ Med J

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Objectives: Ataxia-telangiectasia (A-T) is an autosomal recessive multisystem disorder characterised by cerebellar degeneration, telangiectasia, radiation sensitivity, immunodeficiency, oxidative stress and cancer susceptibility. Epidemiological research has shown that carriers of the heterozygous ataxia-telangiectasia mutated (ATM) gene mutation are radiosensitive to ionising irradiation and have a higher risk of cancers, type 2 diabetes and atherosclerosis. However, there is currently no fast and reliable laboratory-based method to detect heterozygous ATM carriers for family screening and planning purposes. This study therefore aimed to evaluate the ability of a modified G2-assay to identify heterozygous ATM carriers in the families of A-T patients. Methods: This study took place at the Tehran University of Medical Sciences, Tehran, Iran, between February and December 2017 and included 16 A-T patients, their parents (obligate heterozygotes) and 30 healthy controls. All of the subjects underwent individual radiosensitivity (IRS) assessment using a modified caffeine-treated G2-assay with G2-checkpoint abrogation. Results: The mean IRS of the obligate ATM heterozygotes was significantly higher than the healthy controls (55.13% ± 5.84% versus 39.03% ± 6.95%; P <0.001), but significantly lower than the A-T patients (55.13% ± 5.84% versus 87.39% ± 8.29%; P = 0.001). A receiver operating characteristic (ROC) curve analysis of the G2-assay values indicated high sensitivity and specificity, with an area under the ROC curve of 0.97 (95% confidence interval: 0.95–1.00). Conclusion: The modified G2-assay demonstrated adequate precision and relatively high sensitivity and specificity in detecting heterozygous ATM carriers.Keywords: Ataxia-Telangiectasia; Chromosome Breakage; Genetic Carrier Screening; Heterozygote; Radiation Sensitivity; Sensitivity and Specificity.

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Biomarkers and Precision Therapy for Primary Immunodeficiencies: An In Vitro Study Based on Induced Pluripotent Stem Cells From Patients

Genova

Cavion

Lucafò

et al. 2020

Clin Pharma and Therapeutics

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Ataxia telangiectasia (AT) and Aicardi–Goutières syndrome (AGS) are inherited disorders of immunity with prevalent neurological phenotype. Available treatments are only partially effective, and the prognosis is poor. Induced pluripotent stem cells (iPSCs) are obtained by reprogramming patient somatic cells, preserving the donor individual genetic heritage and creating patient‐specific disease models, useful to investigate pathogenesis and drug effects and to develop precision therapies. The aim is to investigate the cytotoxicity of a panel of immunomodulators using iPSCs of patients with AT or different forms of AGS (AGS1, AGS2, and AGS7). iPSCs were obtained by reprogramming AT and AGS patients’ cells and, as a control, the BJ normal human fibroblast line, using Sendai virus. Cytotoxic effects of two drugs proposed to treat respectively AT and AGS (dexamethasone and mepacrine) were tested by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay after 72 hours' exposure. Data were obtained also for other immunomodulatory drugs (thioguanine, mercaptopurine, thalidomide, and lenalidomide). Relative expression of genes involved in the tested drug pathways was analyzed. AGS7‐derived iPSCs displayed altered viability when treated with a low dose of mepacrine and higher expression of cyclic guanosine monophosphate–adenosine monophosphate synthase, which is the main target for mepacrine action. AGS7‐derived iPSCs were also more sensitive to thioguanine, while AGS2 and AT iPSCs were less sensitive to this medication than the BJ‐iPSC. All iPSCs were equally sensitive to mercaptopurine and resistant to dexamethasone, thalidomide, and lenalidomide. This work establishes an innovative in vitro model that is useful to investigate the mechanisms of drugs potentially effective in AT and AGS.

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Inflammation, a significant player of Ataxia–Telangiectasia pathogenesis?

Abstract: Ataxia-Telangiectasia Mutated (ATM), a master regulator of the DNA damage response is the protein known to be associated with A-T and has a complex nuclear and cytoplasmic role. Loss of ATM function may induce immune deregulation and systemic inflammation.

Cited by 39 publications

References 155 publications

The Role of the DNA Damage Response in Ataxia-Telangiectasia Syndrome

The Role of the DNA Damage Response in Ataxia-Telangiectasia Syndrome

Individual Radiosensitivity Assessment of the Families of Ataxia-Telangiectasia Patients by G2-Checkpoint Abrogation

Biomarkers and Precision Therapy for Primary Immunodeficiencies: An In Vitro Study Based on Induced Pluripotent Stem Cells From Patients

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