title: NADPH oxidase 4 is a critical mediator in Ataxia telangiectasia disease.
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.
authors: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and weyemiurbain@yahoo.fr bonnerw@mail.nih.gov.
authors: Urbain
authors: U
authors: Weyemi
authors: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors: Christophe E
authors: CE
authors: Redon
authors: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors: Towqir
authors: T
authors: Aziz
authors: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors: Rohini
authors: R
authors: Choudhuri
authors: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors: Daisuke
authors: D
authors: Maeda
authors: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors: Palak R
authors: PR
authors: Parekh
authors: Department of Dermatology and Atlanta Veterans Administration Medical Center, Emory University, Atlanta, GA 30322.
authors: Michael Y
authors: MY
authors: Bonner
authors: Department of Dermatology and Atlanta Veterans Administration Medical Center, Emory University, Atlanta, GA 30322.
authors: Jack L
authors: JL
authors: Arbiser
authors: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and weyemiurbain@yahoo.fr bonnerw@mail.nih.gov.
authors: William M
authors: WM
authors: Bonner
mesh_terms: D000328:Adult; D000818:Animals; D001260:Ataxia Telangiectasia / Q000201:enzymology* / Q000473:pathology; D004249:DNA Damage; D004261:DNA Replication; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human
keywords: DNA damage; NOX4; ROS; ataxia telangiectasia; neurodegeneration
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