Accumulation of DNA Damage and Reduced Levels of Nicotine Adenine Dinucleotide in the Brains of Atm-deficient Mice

Abstract

Ataxia-telangiectasia (A-T) is a human genetic disorder caused by mutational inactivation of the ATM gene. A-T patients display a pleiotropic phenotype, in which a major neurological feature is progressive ataxia due to degeneration of cerebellar Purkinje and granule neurons. Disruption of the mouse Atm locus creates a murine model of A-T that exhibits most of the clinical and cellular features of the human disease, but the neurological phenotype is barely expressed. We present evidence for the accumulation of DNA strand breaks in the brains of Atm(-/-), supporting the notion that ATM plays a major role in maintaining genomic stability. We also show a perturbation of the steady state levels of pyridine nucleotides. There is a significant decrease in both the reduced and the oxidized forms of NAD and in the total levels of NADP(T) and NADP(+) in the brains of Atm(-/-) mice. The changes in NAD(T), NADH, NAD(+), NADP(T), and NADP(+) were progressive and observed primarily in the cerebellum of 4-month-old Atm(-/-) mice. Higher rates of mitochondrial respiration were also recorded in 4-month-old Atm(-/-) cerebella. Taken together, our findings support the hypothesis that absence of functional ATM results in continuous stress, which may be an important cause of the degeneration of cerebellar neurons in A-T.

Doxorubicin Activates ATM-dependent Phosphorylation of Multiple Downstream Targets in Part through the Generation of Reactive Oxygen Species

“…Thus, the absence of functional ATM would result in cells under a continuous state of oxidative stress. Consistent with this are observations that A-T cells and tissues exhibit significantly reduced rates of GSH resynthesis following depletion (49) and show reduced levels of nicotine adenine dinucleotide (50) and elevated levels of numerous biomarkers of oxidative damage (51). We demonstrate here that hydroxyl radicals play a role in the rapid activation of ATM and ATM-dependent signaling pathways, which further supports the hypothesized link between ATM function and ROS.…”

Contribution of the Atm Protein to Maintaining Cellular Homeostasis Evidenced by Continuous Activation of the AP-1 Pathway in Atm-deficient Brains

“…DNA damage, especially DSBs, poses a critical threat to the cell. The finding of an accumulation of DNA breaks in Atm-deficient cerebella with no signs of cell death (48) argues in favor of a protective role for AP-1. Our data, on the other hand, does not rule out a pro-apoptotic role for AP-1.…”

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

“…7,10 Besides, ATM is involved in sensing and maintaining the redox status, and indeed cells from patients with A-T exhibit reduced antioxidant capacity and persistent oxidative stress, 29 whereas brains from ATM-deficient mice show enhanced production of ROS and increased markers of oxidative stress. 16 Whether neurodegeneration in A-T primarily arises from the inappropriate response to DNA damage or increased oxidative stress remains to be clearly established.…”

“…Furthermore, brains or astrocytes from ATM-deficient mice present elevated production of ROS and increased activation of the redox-sensitive kinases, ERK1/2. 14,16 Interestingly, the antioxidant N-acetyl-cysteine strongly suppresses ERK signaling and protects Purkinje cells from oxidative stress-induced degeneration. Moreover, dietary supplementation of N-acetyl cysteine (NAC) suppresses the mutational signature indicative of oxidative DNA damage in ATM-deficient mice.…”