## 4 Discussion
### The Cerebellar Transcriptome Profile of ATM-Null Mice at 12 Months of Age  
This cerebellar transcriptome profile was exceptionally informative, probably because protein kinases such as ATM are part of phosphorylation cascades that relay information on membrane events to the nucleus, governing transcriptional responses to stimuli versus stress. Before experiments in a cell culture model of ATM dysfunction validated whether individual dysregulations are reproducible in human, and how they depend on stress, it is important to understand the relevance of these key factors within the complex pathogenesis of cerebellar A-T. Thus, we feel the necessity to discuss the integration of all the strong dysregulations with multiple weaker effects within the same significantly enriched pathway, because often upstream events are small, while subsequent signalling cascades will amplify the fold-changes of downstream molecular events. After identifying relevant changes in upstream coordinators and mechanisms of each affected pathway, it is important to explore how they are connected to ATM and how they overlap with other cerebellar ataxias. This discussion text aims to describe a coherent scenario where the failure of stress responses and the underlying toxic agents can be better understood. To comprehend these observations, it may help to consider the analogies between the cerebellar pathology in A-T on the one hand, versus the common sunburn on the other hand. Ionising radiation and ultraviolet-B (UVB) light are typical causes of DNA-DSB in the nucleus, which are sensed by ATM to coordinate repairs. UVB is also the typical cause of sunburns in skin tissue, where not only DNA-DSB is known to ensue, but also cytoplasmic effects like calcium-dependent excitation with chemokine/cytokine release, vasodilitation, inflammation, pain, and keratinocyte death or carcinogenesis [110; 111]. It is already known that ATM is needed after sunburns to mitigate UVB damage and restore normal cell growth [112; 113; 114], so ATM deficiency is indeed expected to impact on cytoplasmic homeostasis, including prolonged vasodilitation, oedema and pain via peptide-signalling. The present transcriptome data provide the molecular details for a similar scenario of pathomechanism in cerebellar tissue. Regarding the prominent neurotransmission effects of cytosolic ATM, previous investigations had reported it to be key for glutamatergic excitation, while ATR was implicated in a complementary role for inhibitory GABAergic neurotransmission [39]. Indeed, our hypothesis-free microarray profiling observed a widespread profound affection of the glutamatergic pathway, reflected by downregulations of receptors _Grid2_ (which is responsible for Spinocerebellar Ataxia type 18 [115]), _Grid2 ip_[116], _Gri4a_, _Gri2k_, _Grin2c_, _Grm1_ (responsible for autosomal recessive Spinocerebellar Ataxia type 13, and autosomal dominant Spinocereblar Ataxia type 44 [117; 118]) and _Grm4_, the glial high affinity glutamate transporter _Slc1a3_ (encoding EAAT1/GLAST which is responsible for Episodic Ataxia type 6 [119; 120]) and _Slc1a6_ (encoding EAAT4 which is involved in Spinocerebellar Ataxia type 5 [121; 122], the mitochondrial glutamate transporter _Slc25a22_, and an eye-catching contrast between downregulation of transporter _Slc17a7_ (encoding VGLUT1 in parallel fibres of the cerebellar cortex), versus massive upregulation of _Slc17a6_ (encoding VGLUT2 in climbing fibres of the deep cerebellum) [123]. Glutamatergic upregulation also affected _Grm5_, _Grm3_, _Grm8_, _Grin2b_, _Grin3a_, _Grid1_, _Slc1a1_ (encoding EAAT3), _Slc1a2_ (encoding EAAT2/GLT1), _Slc1a4_ (encoding ASCT1), the AMPA-receptor interactor _Nsg2_[124], the glutamate receptor interactor _Grip1_[125], and excitation-repressing _Cnr1_[126].