. Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease mechanism. J Neurosci. 2005 Mar 9;25(10):2522-9. PubMed.

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  1. Ataxia-telangiectasia (A-T)is a disorder that presents with a wide spectrum of phenotypes. Many of these phenotypes, such as radiosensitivity and predisposition to malignancies, can be traced back to the breakdown of cell cycle checkpoints and DNA double-strand break detection due to loss of the A-T mutated (ATM) kinase.

    However, the cause of the progressive neuronal degeneration in A-T has not been identified. In this paper, Yang and Herrup present intriguing data supporting the notion that malfunction of cell cycle checkpoints underlie the neuronal degeneration, as well. The neuronal degeneration is quite specific, involving loss of cerebellar Purkinje and granule cells, with a later degeneration of neurons in striatum and substantia. Yang and Herrup first showed that cell cycle proteins were inappropriately present in affected neurons in postmortem brains of individuals with A-T but were not present in the medial frontal gyrus, which is unaffected in the disorder. They detected cell cycle proteins in the same regions of the brain in ATM knockout mice. These data indirectly supported the idea that neurons in these regions were wrongly entering the cell cycle; this was confirmed by FISH, which showed that DNA replication had occurred in neurons affected in A-T.

    The really brilliant part of this study was the use of ATM knockout mice to determine the specific time during development at which Purkinje cells in the cerebellum begin their abortive cell cycle entry. The authors found that the initiation of unscheduled cell cycle events in the Purkinje cells occurs during a very narrow time window between P10 and P20, a period of time during which the final stages of Purkinje cell development take place. At this time, cell migration and the building of a single-cell layer of Purkinje cells is complete, but dendritic arborization and synaptogenesis have yet to occur. According to the authors, these data suggest that one function of ATM is to protect Purkinje cells from entering the cell cycle during this relatively vulnerable period in their development.

    The beauty of this paper is (1) that it offers a unifying hypothesis for the seemingly disparate phenotypes of A-T, and (2) that, by identifying a specific time during mouse development during which Purkinje cells initiate cell cycle entry, it suggests that individuals with A-T may also evince cell cycle events in these cells during a comparable window of time.