Abstract
Despite that the human autosomal recessive disease ataxia telangiectasia (A-T) is a rare pathology, interest in the function of ataxia-telangiectasia mutated protein (ATM) is extensive. From a clinical point of view, the role of ATM in the central nervous system (CNS) is the most impacting, as motor disability is the predominant symptom affecting A-T patients. Coherently, spino-cerebellar neurodegeneration is the principal hallmark of A-T and other CNS regions such as dentate and olivary nuclei and brain stem are implicated in A-T pathophysiology. Recently, several preclinical studies also highlighted the involvement of ATM in the cerebral cortex and hippocampus, thus extending A-T symptomatology to new brain areas and pathways. Here, we review old and recent evidence that largely demonstrates not only the historical ATM account in DNA damage response and cell cycle regulation, but the multiple pathways through which ATM controls oxidative stress homeostasis, insulin signalling pathways, epigenetic regulation, synaptic transmission, and excitatory–inhibitory balance. We also summarise recent evidence on ATM implication in neurological and cognitive diseases beyond A-T, bringing out ATM as new pathological substrate and potential therapeutic target.
Highlights
ataxia-telangiectasia mutated protein (ATM) belongs to a family of large phosphoprotein kinases found in various organisms and ubiquitously expressed
By immunofluorescence and electrophysiological experiments, they showed that primary hippocampal neurons obtained from Atm heterozygous (Atm+/− ) mouse embryos display an E/I imbalance towards inhibition indicated by the following: (i) a higher frequency of miniature inhibitory post synaptic currents; (ii) an increased number of inhibitory synapses; and (iii) GABAergic system. γ-aminobutyric acid (GABA)-containing synaptic vesicles
ataxia telangiectasia (A-T) is a rare multisystem genetic disorder characterized by severe neurological symptoms and important complications, among which are a compromised immune system, progressive respiratory failure, and increased risk of malignancies
Summary
ATM (ataxia-telangiectasia mutated) belongs to a family of large phosphoprotein kinases found in various organisms and ubiquitously expressed. In 2003, Llorca and colleagues first purified human recombinant ATM protein and ATM–DNA bound complex by single-particle electron microscopy and obtained three-dimensional reconstructions showing that DNA binding to ATM induces a large conformational movement of its arm domain towards the head to form a ring-like structure. This ‘ring’ may help to maintain its interaction with the bound linear DNA [34]. These observations are consistent with ATM owning intrinsic DNA binding activity, indispensable for the ATM fundamental role in DNA damage response (DDR)
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