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[Cancer Research 61, 1849-1854, March 1, 2001]
© 2001 American Association for Cancer Research

Biochemistry and Biophysics

Increased Oxidative Stress in Ataxia Telangiectasia Evidenced by Alterations in Redox State of Brains from Atm-deficient Mice1

Ariel Kamsler2, Dvorah Daily2, Ayala Hochman2, Nora Stern, Yosef Shiloh, Galit Rotman and Ari Barzilai3

Departments of Neurobiochemistry [A. K., D. D., N. S., A. B.], and Biochemistry [A. H.], George S. Wise Faculty of Life Sciences, and Department of Human Genetics and Molecular Medicine, Sackler School of Medicine [Y. S., G. R.], Tel Aviv University, Tel Aviv 69978, Israel

Ataxia-telangiectasia (A-T) is a genetic disorder caused by mutational inactivation of the ATM gene. A-T patients display a pleiotropic phenotype and suffer primarily from progressive ataxia caused by 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 features of the human disease. We previously hypothesized that some aspects of A-T, such as the preferential loss of certain neurons, could result from a continuous state of increased oxidative stress (G. Rotman and Y. Shiloh, Cancer Surv., 29: 285–304, 1997; G. Rotman and Y. Shiloh, BioEssays, 19: 911–917, 1997). The present work tests this hypothesis by analyzing markers of redox state in brains of Atm-deficient mice. We found alterations in the levels of thiol-containing compounds in Atm (-/-) brains, as well as significant changes in the activities of thioredoxin, catalase, and manganese superoxide dismutase in Atm (-/-) cerebella. These changes are indicative of increased levels of reactive oxygen species, which are seen primarily in the cerebellum of Atm-deficient mice. Our findings support the hypothesis that the absence of functional ATM results in oxidative stress, which may be an important cause of the degeneration of cerebellar neurons in A-T.




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