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.

Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome

“…Furthermore, recent studies have indicated alternative, endogenous sources of oxidative stress in A-T, BS and NBS cells including NADPH oxidase 4 (NOX4), oxidised low-density lipoprotein (ox-LDL) or Poly (ADP-ribose) polymerases (PARP-1, PARP-2, PARP-3) (Fig. 2) [47], [48], [59], [65] which may provide new pharmacological strategies for patients.…”

“…In the study, the authors evaluated a relationship between ATM deficiency, oxidative DNA damage, neurodegeneration and cancer susceptibility in A-T disease. They demonstrated that NOX4, which constitutively produces ROS in a gamut of cell types and tissues as well as plays a crucial role in oxidative DNA damage and the subsequent senescence [49], was highly up-regulated in A-T patients, similarly to normal cells with a lack of ATM protein kinase [48]. Additionally, NOX4 correlated with higher oxidative damage and apoptosis.…”

“…Interesting data concerning alternative sources of ROS in A-T were published by Weyemi et al [48], who showed that NADPH oxidase 4 (NOX4) may be a key sensor of oxidative stress in A-T cells. In the study, the authors evaluated a relationship between ATM deficiency, oxidative DNA damage, neurodegeneration and cancer susceptibility in A-T disease.…”

“…Hence, it can be assumed that NOX4 may prove a therapeutic strategy in A-T disease, particularly in progressive cerebellar degeneration (Fig. 2) [48].…”

Neurodegeneration in ataxia‐telangiectasia: Multiple roles of ATM kinase in cellular homeostasis

“…This antioxidant dramatically delayed the onset of thymic lymphomas in Atm-deficient mice and corrected the neurobehavioral defects (Gueven et al, 2006), indicating that oxidative stress is an important contributor to the neurodegenerative and cancer-prone phenotype of A-T. The expression of NADPH oxidase (Nox4), a ROS-generating enzyme, was recently shown to be increased in A-T cells and sections of cerebellum from A-T patients (Weyemi et al, 2015). Elevated oxidative stress is also evident in cultured astrocytes from Atmdeficient mice (Liu et al, 2005;Kim and Wong 2009).…”