## 3 Results
### The Cerebellar Transcriptome Profile of ATM-Null Mice at 12 Months of Age
(**c**,**d**) Gene Ontology (GO) enrichment analysis of downregulated (green graphs) and upregulated (red graphs) transcripts, showing biological processes in the upper panel (prominent enrichment for cellular response to corticotropin-releasing hormone stimulus among downregulated transcripts, prominent enrichment for neurotransmitter loading into synaptic vesicle among upregulated transcripts), molecular functions in the lower panel (prominent enrichment for structural constituent of presynaptic active zone among downregulated transcripts, prominent enrichment for inhibitory extracellular ligand-gated ion channel activity among upregulated transcripts). (**e**) Dysregulation validation via RT-qPCR in these 12-month-old mouse cerebella (WT vs. _Atm_-KO, n = 4 vs. 4) for key factors in ATM interaction, excitability, neurotransmission and neuropeptide signalling. For statistical trends, the precise \(p\)-value was shown. Asterisks represent significance: * = \(p\)\(\leq\) 0.05, ** = \(p\)\(\leq\) 0.01, *** = \(p\)\(\leq\) 0.001, ns = non-significant. Data are displayed as mean \(\pm\) SEM. In the disease context, the transcriptome showed a dysregulated expression with nominal significance for genes responsible for phenotypes of ataxia (compiled according to the Online Mendelian Inheritance of Man database, [[https://www.ncbi.nlm.nih.gov/omim/](https://www.ncbi.nlm.nih.gov/omim/)]([https://www.ncbi.nlm.nih.gov/omim/](https://www.ncbi.nlm.nih.gov/omim/)), accessed on 29 February 2022). Downregulations were observed for _Atm_, _Itpr1_, _Syne1_, _Grid2_, _Grik2_, _Fgf14_, _Rora_, _Gba2_, _Reln_, in good agreement with a previous proteome study of cerebrospinal fluid from A-T patients [67]; a significant enrichment was detected on the STRING webserver for \"abnormal cerebellar granule neuron morphology\" (q = 0.0014) for the cluster of ATM, RORA [74] and GRID2 [75] proteins; an enrichment for \"postsynapse\" (q = 0.0182) was detected for ITPR1 [66; 67; 75; 76], SYNE1, GRID2 [75] and GRIK2 [77]; upregulations were observed for the ataxia genes _Mme_, _Ebf3_, _Vamp1_, _Ppp2r2b_, _Svbp_, without significant enrichment, but VAMP1 being a vesicle-associated factor like ATM. Significant expression changes existed also for genes responsible for the pathogenesis of telangiectasia (upregulation of _Sst_, _Sstr1_, _Sstr2_, _Tac1_, _Tacr1_, _Svbp_) [78; 79; 80; 81], and for general growth (_Sst_, _Sstr1_, _Sstr2_) [82]. The significant dysregulation of ATM interactome components _Atm_, _Nr4a1_ and _Foxo3_/_Foxo1_ (but not the ATM interactome components _Mre11_/_Rad50_/_Nbs1_, nor its downstream effectors _Chk2_ and _Tp53_) argued against neural ATM functions at this cerebellar age in DNA damage repair, instead suggesting osmotic/oxidative/nutrient stress [83; 84; 85]. Interestingly however, the deubiquitinus USP2 was reported recently to function in the ATM/NBS1 interactome [86], and showed strong downregulation within the ATM-null cerebellar transcriptome. Even the relatively weak _Kat5_ induction observed may be relevant, in view of the known role of KAT5-dependent ATM Lys3016 acetylation. Finally, among previously reported ATM phosphorylation target proteins [87; 88; 89] with significant dysregulation (see Table S1 annotations) in the 12-month-old ATM-null mouse cerebellar transcriptome, RTN4 (NOGO-A), DOCK10, FSCN1, SOX10, SEPT9 and CCNL2 were already implicated in glutamatergic synapse and dendrite effects [90; 91; 92; 93; 94; 95]. Unexpectedly, the transcript upregulation concerned all neurotransmitter and neuropeptide pathways, rather than a signalling balance between glutamate-excitation on the one hand versus GABA-inhibition on the other hand [39]. Validation experiments by the independent method RT-qPCR in the remaining cerebellar tissue from these 12-month-old ATM-null and WT mice confirmed these dysregulations for practically all factors studied.