ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes

Abstract

ATM kinase, the product of the ataxia telangiectasia mutated (Atm) gene, is activated by genomic damage. ATM plays a crucial role in cell growth and development. Here we report that primary astrocytes isolated from ATMdeficient mice grow slowly, become senescent, and die in culture. However, before reaching senescence, these primary Atm À/À astrocytes, like Atm À/À lymphocytes, show increased spontaneous DNA synthesis. These astrocytes also show markers of oxidative stress and endoplasmic reticulum (ER) stress, including increased levels of heat shock proteins (HSP70 and GRP78), malondialdehyde adducts, Cu/Zn superoxide dismutase, procaspase 12 cleavage, and redox-sensitive phosphorylation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). In addition, HSP70 and ERK1/2 phosphorylation are upregulated in the cerebella of ATMdeficient mice. This increase in ERK1/2 phosphorylation is seen primarily in cerebellar astrocytes, or Bergmann glia, near degenerating Purkinje cells. ERK1/2 activation and astrogliosis are also found in other parts of the brain, for example, the cortex. We conclude that ATM deficiency induces intrinsic growth defects, oxidative stress, ER stress, and ERKs activation in astrocytes.

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

“…42,43 Astrocyte abnormalities and their influence on Purkinje cells have also been reported in Atm Ϫ/Ϫ cells. 41,44,45 Electron microscopy observations have detected structural activation of glial cells in Atm knockout mice. 46 Ultrastructural alterations in astrocytes have been demonstrated alongside neuronal degenerative processes in Atm Ϫ/Ϫ mice in cerebellar tissue.…”

Retrovirus-Induced Oxidative Stress with Neuroimmunodegeneration Is Suppressed by Antioxidant Treatment with a Refined Monosodium α-Luminol (Galavit)

“…At low concentrations, ROS can stimulate cell proliferation (4,27), but at higher concentrations, they damage cells by oxidizing proteins, DNA, and lipids (20,32) or by initiating apoptotic pathways (12). Oxidative stress has been implicated in the neuropathogeneses of many diseases, such as HIV-associated dementia (17,36,38,39,60), Alzheimer's disease (8,37,51,52), and ataxia telangiectasia (3,6,10,21,31). Many viruses, including retroviruses, initiate oxidative stress in infected cells.…”

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

“…11 Data from ATM-null mice support the notion that the cerebellar degeneration arises from a defective DDR, 12 but consequent to oxidative stress. [13][14][15] As developing neurons are rapidly proliferating and potentially generating high levels of oxidants, which favor the accumulation of DNA lesions, genetic defects of the DDR, by exacerbating genomic instability, may eventually compromise neuron survival particularly at postmitotic level. Patients with A-T show attenuated antioxidant capacity and increased oxidative stress.…”

“…Furthermore, brains or astrocytes from ATM-deficient mice present elevated production of ROS and increased activation of the redox-sensitive kinases, ERK1/2. 14,16 Interestingly, the antioxidant N-acetyl-cysteine strongly suppresses ERK signaling and protects Purkinje cells from oxidative stress-induced degeneration. Moreover, dietary supplementation of N-acetyl cysteine (NAC) suppresses the mutational signature indicative of oxidative DNA damage in ATM-deficient mice.…”