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The Journal of Neuroscience, July 19, 2006, 26(29):7767-7774; doi:10.1523/JNEUROSCI.2055-06.2006

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Neurobiology of Disease
Analysis of the Ataxia Telangiectasia Mutated-Mediated DNA Damage Response in Murine Cerebellar Neurons

Inbal Dar,¹ Sharon Biton,² Yosef Shiloh,² and Ari Barzilai¹

¹Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences and ²The David and Inez Myers Laboratory of Genetic Research, Department of Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

Correspondence should be addressed to Dr. Ari Barzilai, Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Email: barzilai{at}post.tau.ac.il

The DNA damage response is a network of signaling pathways that affects many aspects of cellular metabolism after the induction of DNA damage. The primary transducer of the cellular response to the double-strand break, a highly cytotoxic DNA lesion, is the nuclear protein kinase ataxia telangiectasia (A-T) mutated (ATM), which phosphorylates numerous effectors that play key roles in the damage response pathways. Loss or inactivation of ATM leads to A-T, an autosomal recessive disorder characterized by neuronal degeneration, particularly the loss of cerebellar granule and Purkinje cells, immunodeficiency, genomic instability, radiosensitivity, and cancer predisposition. The reason for the cerebellar degeneration in A-T is not clear. It has been ascribed by several investigators to cytoplasmic functions of ATM that may not be relevant to the DNA damage response. We set out to examine the subcellular localization of ATM and characterize the ATM-mediated damage response in mouse cerebellar neurons. We found that ATM is essentially nuclear in these cells and that various readouts of the ATM-mediated damage response are similar to those seen in commonly used cell lines. These include the autophosphorylation of ATM, which marks its activation, and phosphorylation of several of its downstream substrates. Importantly, all of these responses are detected in the nuclei of granule and Purkinje cells, suggesting that nuclear ATM functions in these cells similar to other cell types. These results support the notion that the cerebellar degeneration in A-T patients results from defective DNA damage response.

Key words: ataxia-telangiectasia; DNA damage response; ATM; cerebellum; Purkinje cells; cerebellar granule neurons

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Received Jan. 12, 2006; revised June 12, 2006; accepted June 13, 2006.

Correspondence should be addressed to Dr. Ari Barzilai, Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Email: barzilai{at}post.tau.ac.il

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