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
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 u...
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MDPI AG
2023-10-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Marina Reichlmeir |
| collection | DOAJ |
| description | 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 <i>Usp2</i>, many non-coding RNAs, ataxia genes <i>Itpr1</i>, <i>Grid2</i>, immediate early genes and immunity factors. Allelic splice changes affected prominently the neuropeptide machinery, e.g., <i>Oprm1</i>. 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. |
| first_indexed | 2024-03-10T21:48:05Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T21:48:05Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-db755476b80843dbad5c7f067ecc1ecd2023-11-19T14:13:17ZengMDPI AGCells2073-44092023-10-011219239910.3390/cells12192399In 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 RNAMarina Reichlmeir0Júlia Canet-Pons1Gabriele Koepf2Wasifa Nurieva3Ruth Pia Duecker4Claudia Doering5Kathryn Abell6Jana Key7Matthew P. Stokes8Stefan Zielen9Ralf Schubert10Zoltán Ivics11Georg Auburger12Goethe University Frankfurt, University Hospital, Clinic of Neurology, Exp. Neurology, Heinrich Hoffmann Str. 7, 60590 Frankfurt am Main, GermanyGoethe University Frankfurt, University Hospital, Clinic of Neurology, Exp. Neurology, Heinrich Hoffmann Str. 7, 60590 Frankfurt am Main, GermanyGoethe University Frankfurt, University Hospital, Clinic of Neurology, Exp. Neurology, Heinrich Hoffmann Str. 7, 60590 Frankfurt am Main, GermanyTransposition and Genome Engineering, Research Centre of the Division of Hematology, Gene and Cell Therapy, Paul Ehrlich Institute, 63225 Langen, GermanyDivision of Pediatrics, Pulmonology, Allergology, Infectious Diseases and Gastroenterology, Children’s Hospital, University Hospital, Goethe-University, 60590 Frankfurt am Main, GermanyDr. Senckenberg Institute of Pathology, University Hospital Frankfurt, 60590 Frankfurt am Main, GermanyCell Signaling Technology, Inc., Danvers, MA 01923, USAGoethe University Frankfurt, University Hospital, Clinic of Neurology, Exp. Neurology, Heinrich Hoffmann Str. 7, 60590 Frankfurt am Main, GermanyCell Signaling Technology, Inc., Danvers, MA 01923, USADivision of Pediatrics, Pulmonology, Allergology, Infectious Diseases and Gastroenterology, Children’s Hospital, University Hospital, Goethe-University, 60590 Frankfurt am Main, GermanyDivision of Pediatrics, Pulmonology, Allergology, Infectious Diseases and Gastroenterology, Children’s Hospital, University Hospital, Goethe-University, 60590 Frankfurt am Main, GermanyTransposition and Genome Engineering, Research Centre of the Division of Hematology, Gene and Cell Therapy, Paul Ehrlich Institute, 63225 Langen, GermanyGoethe University Frankfurt, University Hospital, Clinic of Neurology, Exp. Neurology, Heinrich Hoffmann Str. 7, 60590 Frankfurt am Main, GermanyThe 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 <i>Usp2</i>, many non-coding RNAs, ataxia genes <i>Itpr1</i>, <i>Grid2</i>, immediate early genes and immunity factors. Allelic splice changes affected prominently the neuropeptide machinery, e.g., <i>Oprm1</i>. 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.https://www.mdpi.com/2073-4409/12/19/2399cerebellar ataxiacytoplasmic ATMsynaptic pathology |
| spellingShingle | 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 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 cerebellar ataxia cytoplasmic ATM synaptic pathology |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | cerebellar ataxia cytoplasmic ATM synaptic pathology |
| url | https://www.mdpi.com/2073-4409/12/19/2399 |
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