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- Title
In Cerebellar Atrophy of 12-Month-Old ATM-Null Mice, Transcriptome Upregulations Concern Most Neurotransmission and Neuropeptide Pathways, While Downregulations Affect Prominently Itpr1, Usp2 and Non-Coding RNA.
- Authors
Reichlmeir, Marina; Canet-Pons, Júlia; Koepf, Gabriele; Nurieva, Wasifa; Duecker, Ruth Pia; Doering, Claudia; Abell, Kathryn; Key, Jana; Stokes, Matthew P.; Zielen, Stefan; Schubert, Ralf; Ivics, Zoltán; Auburger, Georg
- Abstract
The autosomal recessive disorder Ataxia-Telangiectasia is caused by a dysfunction of the stress response protein, ATM. In the nucleus of proliferating cells, ATM senses DNA double-strand breaks and coordinates their repair. This role explains T-cell dysfunction and tumour risk. However, it remains unclear whether this function is relevant for postmitotic neurons and underlies cerebellar atrophy, since ATM is cytoplasmic in postmitotic neurons. Here, we used ATM-null mice that survived early immune deficits via bone-marrow transplantation, and that reached initial neurodegeneration stages at 12 months of age. Global cerebellar transcriptomics demonstrated that ATM depletion triggered upregulations in most neurotransmission and neuropeptide systems. Downregulated transcripts were found for the ATM interactome component Usp2, many non-coding RNAs, ataxia genes Itpr1, Grid2, immediate early genes and immunity factors. Allelic splice changes affected prominently the neuropeptide machinery, e.g., Oprm1. Validation experiments with stressors were performed in human neuroblastoma cells, where ATM was localised only to cytoplasm, similar to the brain. Effect confirmation in SH-SY5Y cells occurred after ATM depletion and osmotic stress better than nutrient/oxidative stress, but not after ATM kinase inhibition or DNA stressor bleomycin. Overall, we provide pioneer observations from a faithful A-T mouse model, which suggest general changes in synaptic and dense-core vesicle stress adaptation.
- Subjects
NEURAL transmission; NON-coding RNA; DOUBLE-strand DNA breaks; SYNAPTIC vesicles; ATROPHY; TRANSCRIPTOMES; NEUROPEPTIDES; NEUROPEPTIDE Y
- Publication
Cells (2073-4409), 2023, Vol 12, Issue 19, p2399
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells12192399