## 4 Discussion
### The Cerebellar Transcriptome Profile of ATM-Null Mice at 12 Months of Age
On the one hand, increased transcript levels were documented for _Tgfr01_, _Tgfr02_, _Pdgrra_ (with ligand _Pdgrc_), _Epha4_, _Epha5_, _Epha5_ (with ligands _Efra2_, _Efna3_, _Efna5_), _Fgr3_ (with ligands _Fgf18_ and _Fgf5_), _Fgf1 pp2_, _Csf1r_, _Bmpr1b_, _Lift_, _Atp2b4_, _Tuffsf13c_, _Tuffsf21_, _Fzd8_, _Sfrp5_, _Kdr_, and ligands _Bmp2_, _Fgf13_, _Efnb3_, _Ill8_, _Ill33_, _Il34_, _Igf1_ without their receptors. On the other hand, a smaller number of conversely decreased transcript levels were documented for _Fzd4_ (with downregulated ligands _Wnt3_, _Wnt7a_), _Igf2r_ (with downregulated ligand _Igf2_), _Igfr1r_, _Epha3_, _Pdgrf1_, _Sftp1_, _Kit_, _Socs7_, _Il2 orb_, and ligands _Bmp1_, _Bmp7_, _Fgf14_, _Ill6_ without their corresponding receptor. Thus, while a systematic effect of ATM on all cytokines and neurotrophins is doubtful, specifically the deficits of _Ntf3_ and _Ntrk3_ are relevant for the survival of cerebellar granule neurons in a mechanism via Phospho-inositol-3'-kinase (PI3K). Importantly, the vesicle release of neurotransmitters, neuropeptides and neurotrophin-3 has a common upstream mediator in _Cadps2_, which showed decreased cerebellar mRNA levels [151; 152; 153; 154; 155; 156]. The balance between neurotrophin support and glutamate neurotoxicity is known to be critical also for the survival of Purkinje neurons [157; 158; 159; 160]. What other pathways were impacted in several components across the cerebellar transcriptome profile of ATM-null mice, given that the hypothesis-free global transcriptomics approach might give novel clues to understanding A-T pathogenesis better? Second messengers downstream from neuropeptide receptors appeared altered, in view of the G-protein signalling factors _Rgs4_, _Rasgrf2_ and _Gpr165_ upregulates [131; 161; 162], and the dysregulation of calcium modulators _Necab1_ (up) [163] versus _Itpr1_ (down, its loss-of-function being the cause of autosomal dominant Spinocerebellar Atakia types 15 and 29, as well as autoimmune cerebellar ataxia) [164; 57; 165; 166]. The decreased mRNA levels of inositol-trisphosphate receptor _Itpr1_, and of _Cadps2_ (the Ca2+-dependent release activator for neurotransmitters, neuropeptides and neurotrophins), might be underlying contributors to this generalised pathology, given that loss-of-function of both downregulated factors results in cerebellar ataxia [167; 168; 169; 154; 164]. As further coordinators of pathology that are potentially upstream, the deficits of inositol-triphosphate-associated _Astr2_, _Sor11_, and _Mpp4_ levels could lead to inappropriate localisation of membrane proteins away from the tip of neural processes [170; 171]. Regarding upstream factors within the protein interactome of ATM, the following dysregulations deserve discussion: As a key modulator much farther upstream in the path-mechanism, the increased levels of ATM interactor _Atmin_ mRNA probably represent a compensatory response to ATM dysfunction, possibly affecting synaptic adhesion [172; 173]. The _Atmin_ upregulation upon ATM deficiency was unexpected, since both factors were thought to stabilise each other, with ATMIN levels being reduced upon ATM decrease, and vice versa [60; 83]. The ATM-interacting MRN complex responsible for DNA damage signalling did not show any changed mRNA levels, but the NBS1 stabilising factor _Usp2_ mRNA displayed a downregulation of similar effect size and significance as _Att_ mRNA [86]. USP2-null mice show impaired motor coordination and balance [174], so its deficiency in an ATM-null cerebellum might contribute to ataxia pathogenesis. This debujutinase is also known as a regulator of circadian clock components [175], and indeed several USP2 effectors also showed deficient transcript levels, such as _Cry1_ and _Cry2_. In view of the role of KAT5 for the regulation of ATM activity, it may also be relevant that a transcript reduction in our dataset was observed for the KAT5-dependent kinase _Chka_, which is responsible for phospholipid biosynthesis [176; 177].