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Oxidative Stress Is Responsible for Deficient Survival and Dendritogenesis in Purkinje Neurons from Ataxia-Telangiectasia Mutated Mutant Mice

2003; Society for Neuroscience; Volume: 23; Issue: 36 Linguagem: Inglês

10.1523/jneurosci.23-36-11453.2003

1529-2401

Philip Chen, Cheng Peng, John Luff, Kevin Spring, Dianne Watters, Steven E. Bottle, Shigeki Furuya, Martin F. Lavin,

Carcinogens and Genotoxicity Assessment

Atm gene-disrupted mice recapitulate the majority of characteristics observed in patients with the genetic disorder ataxia-telangiectasia (A-T). However, although they exhibit defects in neuromotor function and a distinct neurological phenotype, they do not show the progressive neurodegeneration seen in human patients, but there is evidence that ataxia-telangiectasia mutated (Atm)-deficient animals have elevated levels of oxidized macromolecules and some neuropathology. We report here that in vitro survival of cerebellar Purkinje cells from both Atm "knock-out" and Atm "knock-in" mice was significantly reduced compared with their wild-type littermates. Although most of the Purkinje neurons from wild-type mice exhibited extensive dendritic elongation and branching under these conditions, most neurons from Atm-deficient mice had dramatically reduced dendritic branching. An antioxidant (isoindoline nitroxide) prevented Purkinje cell death in Atm-deficient mice and enhanced dendritogenesis to wild-type levels. Furthermore, administration of the antioxidant throughout pregnancy had a small enhancing effect on Purkinje neuron survival in Atm gene-disrupted animals and protected against oxidative stress in older animals. These data provide strong evidence for a defect in the cerebellum of Atm-deficient mice and suggest that oxidative stress contributes to this phenotype.