Kai Treuner

Failed Clearance of Aneuploid Embryonic Neural Progenitor Cells Leads to Excess Aneuploidy in the Atm-Deficient But Not the Trp53-Deficient Adult Cerebral Cortex

Aneuploid neurons populate the normal adult brain, but the cause and the consequence of chromosome abnormalities in the CNS are poorly defined. In the adult cerebral cortex of three genetic mutants, one of which is a mouse model of the human neurodegenerative disease ataxia-telangiectasia (A-T), we observed divergent levels of sex chromosome (XY) aneuploidy. Although both A-T mutated (Atm)- and transformation related protein 53 (Trp53)-dependent mechanisms are thought to clear newly postmitotic neurons with chromosome abnormalities, we found a 38% increase in the prevalence of XY aneuploidy in the adult Atm-/- cerebral cortex and a dramatic 78% decrease in Trp53-/- mutant mice. A similar 43% decrease in adult XY aneuploidy was observed in DNA repair-deficient Xrcc5-/- mutants. Additional investigation found an elevated incidence of aneuploid embryonic neural progenitor cells (NPCs) in all three mutants, but elevated apoptosis, a likely fate of embryonic NPCs with severe chromosome abnormalities, was observed only in Xrcc5-/- mutants. These data lend increasing support to the hypothesis that hereditary mutations such as ATM-deficiency, which render abnormal cells resistant to developmental clearance, can lead to late-manifesting human neurological disorders.

Loss of Rad52 partially rescues tumorigenesis and T-cell maturation in Atm -deficient mice

Ataxia Telangiectasia (A-T) is an autosomal recessive disease caused by loss of function of the protein kinase ATM. Atm-deficient mice display several phenotypes consistent with the human disease, including predisposition to cancer, growth retardation, cell-proliferation defects and infertility. A-T patients have a several hundred fold increased risk of developing lymphomas and leukemias, which are typically highly invasive. By reducing homologous recombination through genetic deletion of the Rad52 protein, we were able to decrease substantially the development of T-cell lymphomas in Atm−/− mice, resulting in an increased life span of the double mutant mice. Additionally, we were able to partially rescue the T-cell development of Atm−/− mice. Other phenotypes, including growth defects, genomic instability, infertility and radiosensitivity, were not rescued. Our results suggest that excessive recombination is an important contributor to tumorigenesis in A-T.

DNA instability in the brain: survival of the 'fittest'

A new mouse model suggests that genomic instability leads to neuronal cell death in Nijmegen breakage syndrome—a neurological disease associated with predisposition to cancer. Impairing ATM or p53 function in the mice holds cell death at bay, restoring normal neurological function despite persistent genetic abnormalities (pages 538–544).

Chapter 21 – Ataxia-Telangiectasia

Publisher Summary Ataxia-Telangiectasia (A-T) is an autosomal recessive pleiotropic disease caused by mutations in the gene ataxia telangiectasia mutated (ATM). Affected children present as toddlers with truncal ataxia and oculomotor disturbances. The disease proceeds relentlessly with progressive neuro degeneration involving the cerebellum and multiple other brain regions leading to severe neurological compromise and death between 20–30 years of age. Patients also present with dilated blood vessels in the eyes and on the skin (telangiectasia), have immunodeficiency, are infertile, and more than one-third of the patients develop cancer. Patients are hypersensitive to ionizing radiation (IR) and reagents that cause DNA double strand breaks (DSBs). Patients with Nijmegen breakage syndrome exhibit several similarities to A-T patients. They show extreme radiation sensitivity, radioresistant DNA synthesis (RDS), chromosomal instability, and predisposition to cancer. ATLD is characterized by radiation sensitivity, RDS, and progressive cerebellar degeneration, although the severity of the disease seems to markedly different. Unfortunately, the precise clinical characteristics of these patients remain to be established, in particular the nature of the progressive neurological dysfunction.