Dramatic extension of tumor latency and correction of neurobehavioral phenotype in Atm-mutant mice with a nitroxide antioxidant

Gueven, Nuri; Luff, John; Peng, Cheng; Hosokawa, Kazuyuki; Bottle, Steven E.; Lavin, Martin F.

doi:10.1016/j.freeradbiomed.2006.06.018

Cited by 66 publications

(55 citation statements)

References 33 publications

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“…A recent study by Lavin and co-workers showed that treating the Atm −/− mice with an antioxidant produced dramatic improvements on some behavioral tests of balance and motor coordination [93]. For additional discussion of this work, as well as other therapeutic strategies for AT that might be applicable to other related disease see [94].…”

Section: Implications For Treatment and Therapymentioning

confidence: 99%

“…However, the complex phenotypes of human diseases resulting from DNA repair gene mutations may involve interactions between different cell types in the body. Therefore, mouse models are clearly valuable, particularly to the extent that they can recapitulate the human neurologic disease and be used to test therapies [93]. On the other hand, as illustrated by the absence of a neurologic phenotype in the Trex −/− mouse, some disease mechanisms in humans may be species specific.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

2008

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The classic model for neurodegeneration due to mutations in DNA repair genes holds that DNA damage accumulates in the absence of repair, resulting in the death of neurons. This model was originally put forth to explain the dramatic loss of neurons observed in patients with xeroderma pigmentosum neurologic disease, and is likely to be valid for other neurode-generative diseases due to mutations in DNA repair genes. However, in trichiothiodystrophy (TTD), Aicardi-Goutières syndrome (AGS), and Cockayne syndrome (CS), abnormal myelin is the most prominent neuropathological feature. Myelin is synthesized by specific types of glial cells called oligodendrocytes. In this review, we focus on new studies that illustrate two disease mechanisms for myelin defects resulting from mutations in DNA repair genes, both of which are fundamentally different than the classic model described above. First, studies using the TTD mouse model indicate that TFIIH acts as a co-activator for thyroid hormone-dependent gene expression in the brain, and that a causative XPD mutation in TTD results in reduction of this co-activator function and a dysregulation of myelin-related gene expression. Second, in AGS, which is caused by mutations in either TREX1 or RNASEH2, recent evidence indicates that failure to degrade nucleic acids produced during S-phase triggers activation of the innate immune system, resulting in myelin defects and calcification of the brain. Strikingly, both myelin defects and brain calcification are both prominent features of CS neurologic disease. The similar neuropathology in CS and AGS seems unlikely to be due to the loss of a common DNA repair function, and based on the evidence in the literature, we propose that vascular abnormalities may be part of the mechanism that is common to both diseases. In summary, while the classic DNA damage accumulation model is applicable to the neuronal death due to defective DNA repair, the myelination defects and brain calcification seem to be better explained by quite different mechanisms. We discuss the implications of these different disease mechanisms for the rational development of treatments and therapies.

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Section: Implications For Treatment and Therapymentioning

confidence: 99%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

2008

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“…Tempol decreased the DCF intensity indicating a reduction of ROS. In another study, the nitroxide 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) was administered to Atm-deficient mice and again a dramatic delay in the onset of thymic lymphomas was observed [58]. These studies added to the evidence that ROS play an important role in tumorigenesis and that nitroxides can potentially ameliorate this drive.…”

Section: Chemoprevention and Anticancer Activitymentioning

confidence: 99%

The chemistry and biology of nitroxide compounds

Soule

Hyodo

Matsumoto

et al. 2007

Free Radical Biology and Medicine

467

387

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Cyclic nitroxides are a diverse range of stable free radicals that have unique antioxidant properties. Because of their ability to interact with free radicals, they have been used for many years as biophysical tools. During the past 15-20 years, however, many interesting biochemical interactions have been discovered and harnessed for therapeutic applications. Biologically relevant effects of nitroxides have been described including their ability to degrade superoxide and peroxide, inhibit Fenton reactions and undergo radical-radical recombination. Cellular studies defined the activity of nitroxides in vitro. By modifying oxidative stress and altering the redox status of tissues, nitroxides have been found to interact with and alter many metabolic processes. These interactions can be exploited for therapeutic and research use including protection against ionizing radiation, as probes in functional magnetic resonance imaging, cancer prevention and treatment, control of hypertension and weight, and protection from damage resulting from ischemia/reperfusion injury. While much remains to be done, many applications have been well studied and some are presently being tested in clinical trials. The therapeutic and research uses of nitroxide compounds are reviewed here with a focus on the progress from initial development to modern trials.

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“…11 Data from ATM-null mice support the notion that the cerebellar degeneration arises from a defective DDR, 12 but consequent to oxidative stress. [13][14][15] As developing neurons are rapidly proliferating and potentially generating high levels of oxidants, which favor the accumulation of DNA lesions, genetic defects of the DDR, by exacerbating genomic instability, may eventually compromise neuron survival particularly at postmitotic level. Patients with A-T show attenuated antioxidant capacity and increased oxidative stress.…”

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confidence: 99%

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

et al. 2009

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Ataxia-telangiectasia (A-T) is a neurodegenerative disorder caused by defects in the ATM kinase, a component of the DNA-damage response (DDR). Here, we employed an immortalized human neural stem-cell line (ihNSC) capable of differentiating in vitro into neurons, oligodendrocytes and astrocytes to assess the ATM-dependent response and outcome of ATM ablation. The time-dependent differentiation of ihNSC was accompanied by an upregulation of ATM and DNA-PK, sharp downregulation of ATR and Chk1, transient induction of p53 and by the onset of apoptosis in a fraction of cells. The response to ionizing radiation (IR)-induced DNA lesions was normal, as attested by the phosphorylation of ATM and some of its substrates (e.g., Nbs1, Smc1, Chk2 and p53), and by the kinetics of c-H2AX nuclear foci formation. Depletion in these cells of ATM by shRNA interference (shATM) attenuated the differentiation-associated apoptosis and response to IR, but left unaffected the growth, self-renewal and genomic stability. shATM cells generated a normal number of MAP2/b-tubulin III þ neurons, but a reduced number of GalC þ oligodendrocytes, which were nevertheless more susceptible to oxidative stress. Altogether, these findings highlight the potential of ihNSCs as an in vitro model system to thoroughly assess, besides ATM, the role of DDR genes in neurogenesis and/or neurodegeneration.

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Dramatic extension of tumor latency and correction of neurobehavioral phenotype in Atm-mutant mice with a nitroxide antioxidant

Cited by 66 publications

References 33 publications

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

The chemistry and biology of nitroxide compounds

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

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