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The Journal of Neuroscience, December 10, 2003, 23(36):11453-11460

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

Philip Chen,¹ Cheng Peng,¹ John Luff,¹ Kevin Spring,¹ Dianne Watters,² Steven Bottle,³ Shigeki Furuya,⁴ and Martin F. Lavin^1,5

¹The Queensland Institute of Medical Research, Royal Brisbane Hospital, Herston, Queensland 4029, Australia, ²School of Biomolecular and Biomedical Sciences, Griffith University, Nathan Campus, Brisbane, Queensland 4111, Australia, ³School of Physical Sciences, Queensland University of Technology, Brisbane 4001, Australia, ⁴National Circuit Mechanisms Research Group, Brain Science Institute, RIKEN, Saitama, 351-0198, Japan, and ⁵Department of Surgery, University of Queensland, Royal Brisbane Hospital, Herston, Queensland 4029, Australia

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.

Key words: ataxia-telangiectasia; neurodegeneration; Purkinje neurons; oxidative stress; cell cultures; Atm mutant mice

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Received July 9, 2003; revised September 30, 2003; accepted October 3, 2003.

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