In immunoblots of nuclear versus cytoplasmic protein extracts from mice at maximal age 6 weeks, cytoplasmic ATM was solidly detected in the cerebellum but not in the spleen or thymus, while nuclear ATM remained strongly predominant even in the cerebellum at this young age [27]. However, this might change in adult animals when neuronal circuitry and myelination are complete. Regarding the ATM interactome, it is important to note that ATM is a member of the PIK family (phosphooinositide 3-kinase-related kinases), which is anchored at membranes via the FATC domain [28; 29]. Most other PIKKs phosphorylate inositol lipids, while ATM and its homolog ATR were reported to target selectively serine or threonine followed by glutamine (SQ-TQ motif) amino acids within several hundred protein substrates identified so far [17]. ATM mutation affects the membrane interface between endoplasmic reticulum and mitochondria [30], as well as endosomes, peroxisomes, lysosomal and autophagic vesicles [24; 31; 32]. Upon endosomal association, ATM was found to interact with beta-Adaptin (AP1B1/AP2B1) and Neuronal Adaptin-like beta-subunit Protein (beta-NAP) [33]. The cytoplasmic portion of ATM prompted different studies about altered pathways there, and about additional ATM functions [34; 35; 36; 37], but a conclusive mechanistic scenario has not emerged as yet. The association of ATM with presynaptic neurotransmitter-containing vesicles was also demonstrated [38], with a preferential binding to excitatory vesicles that contain VGLUT1 as a glutamate transporter to control their quantal size [39; 40]. Pre- and post-synaptic swelling and loss of cytosolic texture were detectable by electron microscopy in ATM-null mouse cerebellar cortex already at age 2 months [41]. Cerebellar Purkinje pathology involves defects in calcium spike bursts and calcium currents, as well as the progressive reduction in spontaneous action potential firing frequency, from the age of 6 weeks to their maximal lifespan of 5 months in the absence of treatment [42]. Overall, the absence of ATM protein from its physiological membrane association in neuronal cytoplasm clearly triggers age-associated neurodegeneration, but it remains unclear to what degree ATM acts via its physical interactions with membrane lipids and proteins, versus its protein kinase activity. With regard to ATM presence as opposed to its kinase activity, it is important to know that mice expressing the kinase-deficient ATM exhibit an early embryonic lethality phenotype [43; 44], whereas ATM-null mice are viable and their affection becomes apparent only for the immune system at early adult ages. This might suggest that the absence of ATM is sensed and mostly compensated for by cells, whereas substituting ATM function becomes much more difficult if it occupies the correct positions within its interactome, but fails to signal upon stress events. In mice, the ATM deficiency usually results in a shortened survival of haematopoietic cells, early frequent occurrence of lymphomas, and a lifespan over a few months only, so the manifestation of ataxia and cerebellar atrophy is usually prevented by an untimely death due to the immune deficit [41; 45]. A dramatic extension of life expectancy from 4 to 12 months was achieved by bone-marrow transplants in ATM-null mice, and in such animals a decreased cerebellar size index was observed upon brain imaging at the age of 8 months [46]. Activation of normally inactive homodimeric ATM is differently regulated, when distinct stressors are applied. Variance in post-translational modifications and interaction partners of ATM exist. The DNA damage-dependent activation (e.g., by the DNA strand-breaking drug bleomycin, or ionizing radiation) involves Ser1981 autophosphorylation, Lys3016 acetylation by KAT5, interaction with the MRN protein complex (MRE11, RAD50 and NBS1) and ATM monomerisation [47; 48; 49].