TRANSLATIONAL IMPACT

Abstract

Ataxia telangiectasia (A-T) is a rare, recessive, neurodegenerative disease, with symptoms that normally appear in early childhood. Initial indications are usually ataxia (a lack of muscle control leading to loss of balance and coordination) and telangiectasia (tiny red veins, which are most noticeable on the whites of the eyes). The most serious clinical problem is loss of Purkinje cells, leading to degeneration of the cerebellum (the body’s motor control centre). About 70% of sufferers also have thymic hypoplasia and a compromised immune system. Patients are also highly sensitive to X-irradiation and are susceptible to malignant tumors. Currently, there is no cure, nor any treatment that halts the progression of the disease.A-T is caused by mutation of the ATM gene, which encodes a ubiquitous 370-kD serine-threonine kinase that is essential for normal repair of double-stranded DNA breaks; loss of ATM function results in DNA instability. However, there are atypical cases of A-T in which ATM is completely lacking: in these cases, DNA repair is defective, but symptoms are mild. These cases suggest that the severity of the neurological component of A-T might be due to a combination of defects, some of which are unknown.ATM phosphorylates several hundred substrates, including the transcription factor ZFHX3 (also known as ATBF1). In this study, the authors show that ZFHX3 is indirectly induced by ATM, and that ZFHX3 in turn induces the membrane tyrosine kinase PDGFRB, which is a survival factor in neurons. Neurons are highly susceptible to oxidative stress owing to their high rate of oxidative metabolism and low levels of antioxidant enzymes, and, in A-T mutant mice, oxidative stress is one of the major causes of Purkinje cell death. Inhibition of PDGFRB activity results in loss of ATM activity under conditions of oxidative stress, but not genotoxic stress, suggesting a means whereby ATM can rapidly autoregulate its activity.To induce oxidative stress, mice were treated with kainic acid, resulting in predominantly cytoplasmic activation of ATM in the cerebral cortex, hippocampus and deep cerebellar nuclei (DCN). The authors propose that activation of ATM in the cytoplasm might play a role in autophagic protection of neurons against oxidative stress.The signaling pathway from ATM to PDGFRB described here might be important in determining the response of neurons to oxidative stress, and be one of the hitherto unknown factors contributing to A-T. Therefore, targeting the action of PDGFRB might yield therapies that protect neurons against oxidative stress. The use of kainic acid to induce neuronal stress in mouse brains will also mean that Atm-deficient mice can be used to observe the early onset of neurodegeneration in the cerebellum; currently, the mice cannot be used as a model, because they die of cancer within 3–4 months, before manifestation of neurodegenerative disease. Kainic acid treatment will therefore be a good experimental tool to speed up screening of effective therapeutics.