Loss of Neuronal Cell Cycle Control in Ataxia-Telangiectasia: A Unified Disease Mechanism

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Abstract
In ataxia-telangiectasia (A-T), the loss of the ataxia-telangiectasia mutated (ATM) kinase leads to a failure of cell cycle checkpoints and DNA double-strand break detection resulting in cellular radiation sensitivity and a predisposition to cancer. There is also a significant loss of neurons, in particular cerebellar granule and Purkinje cells. Mice homozygous for null alleles of atm reproduce the radiation sensitivity and high-tumor incidence of the human disease but show no significant nerve cell loss. Using immunocytochemistry, we found the re-expression of cell cycle proteins in Purkinje cells and striatal neurons in both human and mouse A-T. In the mouse, we used fluorescent in situ hybridization (FISH) to document that DNA replication accompanies the reappearance of these proteins in at-risk neuronal cells. We also found the presence of significant cell cycle activity in the Purkinje cells of the atm+/- heterozygote mouse. The cell cycle events in mouse cerebellum occur primarily during the third postnatal week by both FISH and immunocytochemistry. Thus, the initiation of this ectopic cell division occurs just as the final stages of Purkinje cell development are being completed. These results suggest that loss of cell cycle control represents a common disease mechanism that underlies the defects in the affected tissues in both human and mouse diseases.