Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice.
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.
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
A
A
Kamsler
D
D
Daily
A
A
Hochman
N
N
Stern
Y
Y
Shiloh
G
G
Rotman
A
A
Barzilai
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001260:Ataxia Telangiectasia / Q000201:enzymology / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D002374:Catalase / Q000378:metabolism; D018797:Cell Cycle Proteins; D002531:Cerebellum / Q000201:enzymology / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013687:Telencephalon / Q000201:enzymology / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D000975:Antioxidants; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D013879:Thioredoxins; D002374:Catalase; D013482:Superoxide Dismutase; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D005978:Glutathione; D003545:Cysteine