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J. Biol. Chem., Vol. 277, Issue 1, 602-608, January 4, 2002

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

Nora Stern, Ayala Hochman^§, Naty Zemach, Nir Weizman, Ilan Hammel^¶, Yosef Shiloh, Galit Rotman, and Ari Barzilai^**

From the  Department of Neurobiochemistry, ^§ Department of Biochemistry, George S. Wise Faculty of Life Sciences,  Department of Human Genetics and Molecular Medicine, and ^¶ Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

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.

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