Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Marina Reichlmeir
ORCID logo ,
Júlia Canet-Pons
,
Gabriele Koepf
,
Wasifa Nurieva
ORCID logo ,
Ruth Pia Duecker
,
Claudia Doering
,
Kathryn Abell
,
Jana Key
,
Matthew P. Stokes
,
Stefan Zielen
,
Ralf Schubert
ORCID logo ,
Zóltan Ivics
ORCID logo ,
Georg Auburger
*
Version 1 : Received: 14 September 2023 / Approved: 15 September 2023 / Online: 19 September 2023 (15:15:29 CEST)

A peer-reviewed article of this Preprint also exists.

Reichlmeir, M.; Canet-Pons, J.; Koepf, G.; Nurieva, W.; Duecker, R.P.; Doering, C.; Abell, K.; Key, J.; Stokes, M.P.; Zielen, S.; Schubert, R.; Ivics, Z.; Auburger, G. 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. Cells 2023, 12, 2399. Reichlmeir, M.; Canet-Pons, J.; Koepf, G.; Nurieva, W.; Duecker, R.P.; Doering, C.; Abell, K.; Key, J.; Stokes, M.P.; Zielen, S.; Schubert, R.; Ivics, Z.; Auburger, G. 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. Cells 2023, 12, 2399.

Abstract

The autosomal recessive disorder Ataxia-Telangiectasia is caused by 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 tumor risk. However, it remains unclear whether this function is relevant for postmitotic neurons and underlies the cerebellar atrophy, since ATM is cytoplasmic in postmitotic neurons. Here, we used ATM-null mice that survived early immune deficits by bone-marrow transplantation, and reached initial neurodegeneration stages at 12 months of age. Global cerebellar transcriptomics demonstrated ATM depletion to trigger 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 neuropeptide machinery, e.g. Oprm1. Validation experiments with stressors were performed in human neuroblastoma cells, where ATM localized only to cytoplasm, similar to brain. Effect confirmation in SH-SY5Y cells occurred after ATM depletion and osmotic stress better than nutrient / oxidative stress, 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.

Keywords

cerebellar ataxia; cytoplasmic ATM; synaptic pathology

Subject

Biology and Life Sciences, Neuroscience and Neurology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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