ATM Protein Kinase: Old and New Implications in Neuronal Pathways and Brain Circuitry

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.