## 5 Conclusions  
Overall, our genome-wide RNA profile provided useful knowledge to identify factors that might underlie the growth deficit (somatostatin and neuropeptide-Y) and vasodilation phenotypes (tachykinins and _Ece11_) of A-T, and to define the mechanistic overlap of A-T with the _Itpr1_-triggered monogenic variants of cerebellar ataxia. The data in this project suggested that the presence of cytosolic ATM in postmitotic cerebellar neurons serves as an important modulator of the transcriptional regulation of excitability factors in response to ageing, and to osmotic stress more than nutrient or oxidative stress. Validations in neuroblastoma culture could largely reproduce crucial insights and the prominent alterations found in the cerebellar transcriptome: Strong reduction of _Atm_ levels was reflected in similar strong decreases of its interactor _Usp2_, the mainly Purkinje-neuron-expressed Ca\({}^{2+}\)-excitability modulator _Itpr1_ mRNAs, and immediate-early signalling factors such as _Per1_ and _Nrta1_. Future experiments have to determine to what degree a ubiquitous or selective affection of transcripts in the well-known cerebellar cell types and circuitry pathways exists, as shown in the Graphical Abstract (which contains a scheme from [230] with modifications).  
**Supplementary Materials:** The following supporting information can be downloaded at: [[https://www.mdpi.com/article/10.3390/cells12192399/s1](https://www.mdpi.com/article/10.3390/cells12192399/s1)]([https://www.mdpi.com/article/10.3390/cells12192399/s1](https://www.mdpi.com/article/10.3390/cells12192399/s1)), Figure S1: RT-qPCR validation of cerebellar transcript dysregulations in 1.5-3-month-old ATM-null mice shows early onset of immediate-early mRNA reductions, suggesting insufficient excitability; Figure S2: Modelling stable _ATM_-deficiency in vitro via knockdown in SH-SYSY neuroblastoma cells; Figure S3: Subcellular localisation of ATM to SH-SYSY cytoplasm is unchanged after CQ and BLEO stress; Figure S4: RT-qPCR analysis of the modelling of cerebellar dysregulations in SH-SYSY cells, testing different stressors, as well as ATM deficiency versus kinase inhibition; Table S1: The global transcriptome profile of the ATM-null cerebellum.  
**Author Contributions:** Conceptualisation, M.R., R.S., Z.I. and G.A.; methodology, M.R., J.C.-P., G.K., W.N., R.P.D., C.D., K.A. and J.K.; software, W.N., C.D. and J.K.; validation, M.R., J.C.-P., G.K., W.N., K.A., M.P.S., Z.I. and G.A.; formal analysis, M.P.S., S.Z., R.S., Z.I. and G.A.; investigation, Z.I. and G.A.; resources, R.S. and Z.I.; data curation, C.D., K.A. and M.P.S.; writing--original draft M.R.; writing--review and editing, W.N., S.Z., R.S. and G.A.; visualisation, M.R., J.C.-P., J.K. and G.A.; supervision, Z.I. and G.A.; project administration, G.A.; funding acquisition, S.Z., R.S., Z.I. and G.A. All authors have read and agreed to the published version of the manuscript.  
**Funding:** This research was funded by the Deutsche Forschungsgemeinschaft, grant numbers AU 96/19-1 and IV 21/17-1.  
**Institutional Review Board Statement:** The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of the Regierungsprasidium Darmstadt (protocol code V54-19 c20/15-FK/1034 and date of approval 17 March 2015).  
**Informed Consent Statement:** Not applicable.  
**Data Availability Statement:** The complete gene expression data set was deposited publicly in the Gene Expression Omnibus under accession number GSE241955.  
**Acknowledgments:** We thank [PERSON] and [PERSON] for advice. We are grateful to the staff of the animal facility ZFE at the Goethe University Hospital for technical assistance.  
**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.