Details

Autor(en) / Beteiligte

• Weyemi, Urbain
• Redon, Christophe E.
• Aziz, Towqir
• Choudhuri, Rohini
• Maeda, Daisuke
• Parekh, Palak R.
• Bonner, Michael Y.
• Arbiser, Jack L.
• Bonner, William M.

Titel

NADPH oxidase 4 is a critical mediator in Ataxia telangiectasia disease

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2015-02, Vol.112 (7), p.2121-2126

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

• 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. Significance Ataxia telangiectasia (A-T) is a rare, autosomal recessive disorder characterized by progressive cerebellar degeneration. Oxidative stress is one cause of the symptoms of A-T disease. We report that inactivation of NADPH oxidase 4 (NOX4) reduced ROS, oxidative DNA damage, DNA double-strand breaks and replicative senescence in A-T primary cells. Analyses of A-T patients revealed elevated levels of NOX4 in the cerebellum that also correlated with increased levels of DNA damage and apoptosis. These observations were substantiated by the absence of abnormal NOX4 cerebellar expression in mouse models of A-T disease which do not display cerebellar degeneration. However, injecting A-T mice with NOX4 inhibitor decreased their elevated cancer incidence. Therefore, NOX4 appears as a critical mediator in A-T disease.