In neuronal cells, strong excitation promotes immediate-early gene transcription via DNA-DSB, which are mediated by topoisomerase-1 cleavage complexes (TOP1 cc), and have to be eliminated by ATM activation, otherwise toxic accumulation of R-loops will occur [50; 51]. It is thought that ATM senses TOP1 cc/R-loops and organises their removal, in a process that is impaired upon oxidative damage [17]. Indeed, elevated levels of R-loops were observed in ATM-null mouse testis, but not in brain tissue, at the age of 1 month [52]. Importantly, the R-loop activation of ATM promotes chromatin displacement of late-stage spliceosomes, so the alternative splicing in ATM mutants may be changed in genome-wide manner [53]. Some ATM-dependent changes in RNA processing were reported to be mediated by the nuclear splice regulator SAM68 [54]. Thus, RNA neurotoxicity via R-loops and SAM68, protein aggregation and unbalanced excitability have been proposed to underlie the ataxia and cerebellar atrophy in A-T, in view of similar clinico-pathological findings in other monogenic spinocerebellar ataxias where mutant AOA2, FRDA, ATXN2, ITPR1 trigger similar cytosolic pathways in pathogenesis [17; 55; 56; 57]. However, few other data are available to judge the overlap in pathogenesis between diverse monogenic ataxias, and to decide which other cerebellar ataxias are closest to A-T. In contrast to these mechanisms following DNA and RNA damage, the activation of ATM upon osmotic stress (e.g., by the drug chloroquine, or hypotonic shock) involves its interaction with ATMIN [47; 58]. Furthermore, activation of nuclear ATM via nutrient deprivation (by 2-deoxyglucose exposure) is mediated by the inefficient assembly of a protein complex between the endoplasmic reticulum and mitochondrial membranes, which is composed by IP3R1 (gene symbol \(ITPRI\)), GRP75 (gene symbol \(HSPA9\)), and VDAC1. This inadequate assembly results in impaired release of Ca\({}^{2+}\) and excitability in the human bronchial epithelial cell line HBEC3-KT [30]. Finally, the activation of ATM via oxidative stress (e.g., by the drug sodium arsenite, abbreviated as NaARS, or by hydrogen peroxide H\({}_{2}\)O\({}_{2}\)) involves Cys2991 disulfide bonds linking active ATM homodimers, but appears independent from the MRN complex [59]. Again, ATMIN plays a relevant role in the protection against oxidative stressors [60]. All these mechanistic insights were obtained in cell culture or in young adult animals. Thus, at present it remains completely unclear which of these stressors and molecular response mechanisms would play the prominent role in the cerebellum when the age-associated pathology manifests. For the present study, we analysed cerebellar homogenates from bone-marrow-translated, 12-month-old ATM-null mice, documenting their global transcriptome by oligonucleotide microarrays, in the hope of elucidating the impact of ATM for RNA-mediated stress responses. With this approach, we hoped to answer the following questions: (1) Which impact exists on transcript levels of known ATM interactors, or known ATM phosphorylation substrates? (2) Which dysregulations occur in phosphoinositide pathway membrane factors, in vesicular factors, or in calcium homeostasis factors? (3) To what degree is the altered neuronal excitability reflected by dysregulations of neurotransmission factors or immediate early genes? (4) Were some dysregulations already observed in telangiectasia, in general growth deficit, or selective cerebellar atrophy, e.g., as known disease genes of other cerebellar ataxias? Such findings would define the mechanistic overlap with other genetic disorders. (5) Are there strong dysregulations of novel character outside these already explored pathways? Validation work in vitro with further methods and samples was performed to answer additional questions: (6) Whether ATM in the adult cerebellum is still mostly nuclear with solid cytosolic presence, and if the human neural SH-SYSY cell line is a good model of ATM distribution, was assessed with differential detergent fractionation.