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

Abstract

Ataxia-telangiectasia (A-T) is characterized by neuronal degeneration, cancer, diabetes, immune deficiency, and increased sensitivity to ionizing radiation. A-T is attributed to the deficiency of the protein kinase coded by the ATM (ataxia-telangiectasia mutated) gene. ATM is a sensor of DNA double-strand breaks (DSBs) and signals to cell cycle checkpoints and the DNA repair machinery. ATM phosphorylates numerous substrates and activates many cell-signaling pathways. There has been considerable debate about whether a defective DNA damage response is causative of the neurological aspects of the disease. In proliferating cells, ATM is localized mainly in the nucleus; however, in postmitotic cells such as neurons, ATM is mostly cytoplasmic. Recent studies reveal an increasing number of roles for ATM in the cytoplasm, including activation by oxidative stress. ATM associates with organelles including mitochondria and peroxisomes, both sources of reactive oxygen species (ROS), which have been implicated in neurodegenerative diseases and aging. ATM is also associated with synaptic vesicles and has a role in regulating cellular homeostasis and autophagy. The cytoplasmic roles of ATM provide a new perspective on the neurodegenerative process in A-T. This review will examine the expanding roles of ATM in cellular homeostasis and relate these functions to the complex A-T phenotype.

Multifaceted roles of ATM in autophagy: From nonselective autophagy to selective autophagy

“…57,[59][60][61][62] The accumulation of ROS caused by dysregulation of mitophagy and pexophagy plays a central role in inflammation and chronic diseases, such as atherosclerosis and cancer. 57,[59][60][61][62] The accumulation of ROS caused by dysregulation of mitophagy and pexophagy plays a central role in inflammation and chronic diseases, such as atherosclerosis and cancer.…”

“…57,[59][60][61][62] The accumulation of ROS caused by dysregulation of mitophagy and pexophagy plays a central role in inflammation and chronic diseases, such as atherosclerosis and cancer. 59 Here, we elucidate the mechanisms of selective autophagy, especially those involving ATM. 59 Here, we elucidate the mechanisms of selective autophagy, especially those involving ATM.…”

“…Recently, increasing evidence has demonstrated that ATM plays an important role in selective autophagy, and its dysregulation has resulted in a number of diseases, such as cancer, neurodegeneration, metabolic disorders, ageing, and inflammation. 57,[59][60][61][62] The accumulation of ROS caused by dysregulation of mitophagy and pexophagy plays a central role in inflammation and chronic diseases, such as atherosclerosis and cancer. 57 In addition, ATM-related lipophagy can regulate lipid metabolism to provide the basis for novel therapeutic strategies.…”

“…57 In addition, ATM-related lipophagy can regulate lipid metabolism to provide the basis for novel therapeutic strategies. 59 Here, we elucidate the mechanisms of selective autophagy, especially those involving ATM.…”

Host-dependent induction of disease tolerance to infection by tetracycline antibiotics

“…A low dose of doxycycline, 1.25 and 5 μg/mL, induced a modest increase in ROS levels in HepG2 cells ( Figure S5D), without affecting the mitochondrial mass as revealed by the use of Mitotracker green ( Figure S5E). The ATM kinase, that we previously have shown to be required for the activation of disease tolerance in response to low dose anthracycline treatment (Figueiredo et al, 2013) can be activated by ROS (Choy and Watters, 2018). To test the hypothesis that doxycycline induction of disease tolerance could be mediated by the ROS activation of ATM, we have used AAV8-CRE mediated depletion of ATM in the liver and monitored survival in response to infection.…”