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      NADPH oxidase 4 is a critical mediator in Ataxia telangiectasia disease.

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          Abstract

          Ataxia telangiectasia (A-T), a rare autosomal recessive disorder characterized by progressive cerebellar degeneration and a greatly increased incidence of cancer among other symptoms, is caused by a defective or missing ataxia telangiectasia mutated (ATM) gene. The ATM protein has roles in DNA repair and in the regulation of reactive oxygen species (ROS). Here, we provide, to our knowledge, the first evidence that NADPH oxidase 4 (NOX4) is involved in manifesting A-T disease. We showed that NOX4 expression levels are higher in A-T cells, and that ATM inhibition leads to increased NOX4 expression in normal cells. A-T cells exhibit elevated levels of oxidative DNA damage, DNA double-strand breaks and replicative senescence, all of which are partially abrogated by down-regulation of NOX4 with siRNA. Sections of degenerating cerebelli from A-T patients revealed elevated NOX4 levels. ATM-null mice exhibit A-T disease but they die from cancer before the neurological symptoms are manifested. Injecting Atm-null mice with fulvene-5, a specific inhibitor of NOX4 and NADPH oxidase 2 (NOX2), decreased their elevated cancer incidence to that of the controls. We conclude that, in A-T disease in humans and mice, NOX4 may be critical mediator and targeting it will open up new avenues for therapeutic intervention in neurodegeneration.

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          Author and article information

          Journal
          Proc. Natl. Acad. Sci. U.S.A.
          Proceedings of the National Academy of Sciences of the United States of America
          Proceedings of the National Academy of Sciences
          1091-6490
          0027-8424
          Feb 17 2015
          : 112
          : 7
          Affiliations
          [1 ] Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and weyemiurbain@yahoo.fr bonnerw@mail.nih.gov.
          [2 ] Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
          [3 ] Department of Dermatology and Atlanta Veterans Administration Medical Center, Emory University, Atlanta, GA 30322.
          Article
          1418139112
          10.1073/pnas.1418139112
          4343117
          25646414
          f2ef0549-c9f9-44ca-91cc-f7ff1e4ef85c
          History

          ataxia telangiectasia,neurodegeneration,DNA damage,NOX4,ROS
          ataxia telangiectasia, neurodegeneration, DNA damage, NOX4, ROS

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