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,
Júlia Canet-Pons,
Gabriele Koepf,
Wasifa Nurieva,
Ruth Pia Duecker,
Claudia Doering,
Kathryn Abell,
Jana Key,
Matthew P. Stokes,
Stefan Zielen,
Ralf Schubert,
Zoltán Ivics,
Georg Auburger
Affiliations
Marina Reichlmeir
Goethe University Frankfurt, University Hospital, Clinic of Neurology, Exp. Neurology, Heinrich Hoffmann Str. 7, 60590 Frankfurt am Main, Germany
Júlia Canet-Pons
Goethe University Frankfurt, University Hospital, Clinic of Neurology, Exp. Neurology, Heinrich Hoffmann Str. 7, 60590 Frankfurt am Main, Germany
Gabriele Koepf
Goethe University Frankfurt, University Hospital, Clinic of Neurology, Exp. Neurology, Heinrich Hoffmann Str. 7, 60590 Frankfurt am Main, Germany
Wasifa Nurieva
Transposition and Genome Engineering, Research Centre of the Division of Hematology, Gene and Cell Therapy, Paul Ehrlich Institute, 63225 Langen, Germany
Ruth Pia Duecker
Division of Pediatrics, Pulmonology, Allergology, Infectious Diseases and Gastroenterology, Children’s Hospital, University Hospital, Goethe-University, 60590 Frankfurt am Main, Germany
Claudia Doering
Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany
Kathryn Abell
Cell Signaling Technology, Inc., Danvers, MA 01923, USA
Jana Key
Goethe University Frankfurt, University Hospital, Clinic of Neurology, Exp. Neurology, Heinrich Hoffmann Str. 7, 60590 Frankfurt am Main, Germany
Matthew P. Stokes
Cell Signaling Technology, Inc., Danvers, MA 01923, USA
Stefan Zielen
Division of Pediatrics, Pulmonology, Allergology, Infectious Diseases and Gastroenterology, Children’s Hospital, University Hospital, Goethe-University, 60590 Frankfurt am Main, Germany
Ralf Schubert
Division of Pediatrics, Pulmonology, Allergology, Infectious Diseases and Gastroenterology, Children’s Hospital, University Hospital, Goethe-University, 60590 Frankfurt am Main, Germany
Zoltán Ivics
Transposition and Genome Engineering, Research Centre of the Division of Hematology, Gene and Cell Therapy, Paul Ehrlich Institute, 63225 Langen, Germany
Georg Auburger
Goethe University Frankfurt, University Hospital, Clinic of Neurology, Exp. Neurology, Heinrich Hoffmann Str. 7, 60590 Frankfurt am Main, Germany
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.
