Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons
Decreased rRNA synthesis and nucleolar disruption, known as nucleolar stress, are primary signs of cellular stress associated with aging and neurodegenerative disorders. Silencing of rDNA occurs during early stages of Alzheimer´s disease (AD) and may play a role in dementia. Moreover aberra...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2013-11-01
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| Series: | Frontiers in Cellular Neuroscience |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fncel.2013.00207/full |
| _version_ | 1828404463639986176 |
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| author | Anna eKiryk Grzegorz eKreiner Katharina eSowodniok Jan eRodriguez-Parkitna Aynur eSoenmez Tomasz eGórkiewicz Tomasz eGórkiewicz Holger eBierhoff Marcin eWawrzyniak Artur K Janusz Birgit eLiss Witold eKonopka Günther eSchütz Leszek eKaczmarek Rosanna eParlato Rosanna eParlato Rosanna eParlato |
| author_facet | Anna eKiryk Grzegorz eKreiner Katharina eSowodniok Jan eRodriguez-Parkitna Aynur eSoenmez Tomasz eGórkiewicz Tomasz eGórkiewicz Holger eBierhoff Marcin eWawrzyniak Artur K Janusz Birgit eLiss Witold eKonopka Günther eSchütz Leszek eKaczmarek Rosanna eParlato Rosanna eParlato Rosanna eParlato |
| author_sort | Anna eKiryk |
| collection | DOAJ |
| description | Decreased rRNA synthesis and nucleolar disruption, known as nucleolar stress, are primary signs of cellular stress associated with aging and neurodegenerative disorders. Silencing of rDNA occurs during early stages of Alzheimer´s disease (AD) and may play a role in dementia. Moreover aberrant regulation of the protein synthesis machinery is present in the brain of suicide victims and implicates the epigenetic modulation of rRNA. Recently, we developed unique mouse models characterized by nucleolar stress in neurons. We inhibited RNA polymerase I by genetic ablation of the basal transcription factor TIF-IA in adult hippocampal neurons. Nucleolar stress resulted in progressive neurodegeneration, although with a differential vulnerability within the CA1, CA3 and dentate gyrus. Here, we investigate the consequences of nucleolar stress on learning and memory. The mutant mice show normal performance in the Morris water maze and in other behavioral tests, suggesting the activation of adaptive mechanisms. In fact, we observe a significantly enhanced learning and re-learning corresponding to the initial inhibition of rRNA transcription. This phenomenon is accompanied by aberrant synaptic plasticity. By the analysis of nucleolar function and integrity, we find that the synthesis of rRNA is later restored. Gene expression profiling shows that thirty-six transcripts are differentially expressed in comparison to the control group in absence of neurodegeneration. Additionally, we observe a significant enrichment of the putative serum response factor (SRF) binding sites in the promoters of the genes with changed expression, indicating potential adaptive mechanisms mediated by the mitogen-activated protein kinase pathway. In the dentate gyrus a neurogenetic response might compensate the initial molecular deficits. These results underscore the role of nucleolar stress in neuronal homeostasis and open a new ground for therapeutic strategies aiming at preserving neuronal function. |
| first_indexed | 2024-12-10T10:36:52Z |
| format | Article |
| id | doaj.art-1024a98ede3d4c0e9ef1f2a3ebd2a647 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-10T10:36:52Z |
| publishDate | 2013-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-1024a98ede3d4c0e9ef1f2a3ebd2a6472022-12-22T01:52:24ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022013-11-01710.3389/fncel.2013.0020756962Impaired rRNA synthesis triggers homeostatic responses in hippocampal neuronsAnna eKiryk0Grzegorz eKreiner1Katharina eSowodniok2Jan eRodriguez-Parkitna3Aynur eSoenmez4Tomasz eGórkiewicz5Tomasz eGórkiewicz6Holger eBierhoff7Marcin eWawrzyniak8Artur K Janusz9Birgit eLiss10Witold eKonopka11Günther eSchütz12Leszek eKaczmarek13Rosanna eParlato14Rosanna eParlato15Rosanna eParlato16Nencki Institute of Experimental BiologyPolish Academy of SciencesGerman Cancer Research Center (DKFZ)Polish Academy of SciencesHeidelberg UniversityNencki Institute of Experimental BiologyWarsaw University of Life SciencesGerman Cancer Research Center (DKFZ)Nencki Institute of Experimental BiologyNencki Institute of Experimental BiologyUlm UniversityNencki Institute of Experimental BiologyGerman Cancer Research Center (DKFZ)Nencki Institute of Experimental BiologyGerman Cancer Research Center (DKFZ)Ulm UniversityHeidelberg UniversityDecreased rRNA synthesis and nucleolar disruption, known as nucleolar stress, are primary signs of cellular stress associated with aging and neurodegenerative disorders. Silencing of rDNA occurs during early stages of Alzheimer´s disease (AD) and may play a role in dementia. Moreover aberrant regulation of the protein synthesis machinery is present in the brain of suicide victims and implicates the epigenetic modulation of rRNA. Recently, we developed unique mouse models characterized by nucleolar stress in neurons. We inhibited RNA polymerase I by genetic ablation of the basal transcription factor TIF-IA in adult hippocampal neurons. Nucleolar stress resulted in progressive neurodegeneration, although with a differential vulnerability within the CA1, CA3 and dentate gyrus. Here, we investigate the consequences of nucleolar stress on learning and memory. The mutant mice show normal performance in the Morris water maze and in other behavioral tests, suggesting the activation of adaptive mechanisms. In fact, we observe a significantly enhanced learning and re-learning corresponding to the initial inhibition of rRNA transcription. This phenomenon is accompanied by aberrant synaptic plasticity. By the analysis of nucleolar function and integrity, we find that the synthesis of rRNA is later restored. Gene expression profiling shows that thirty-six transcripts are differentially expressed in comparison to the control group in absence of neurodegeneration. Additionally, we observe a significant enrichment of the putative serum response factor (SRF) binding sites in the promoters of the genes with changed expression, indicating potential adaptive mechanisms mediated by the mitogen-activated protein kinase pathway. In the dentate gyrus a neurogenetic response might compensate the initial molecular deficits. These results underscore the role of nucleolar stress in neuronal homeostasis and open a new ground for therapeutic strategies aiming at preserving neuronal function.http://journal.frontiersin.org/Journal/10.3389/fncel.2013.00207/fullHippocampusNeurogenesislearning and memoryrRNAmTORnucleolus |
| spellingShingle | Anna eKiryk Grzegorz eKreiner Katharina eSowodniok Jan eRodriguez-Parkitna Aynur eSoenmez Tomasz eGórkiewicz Tomasz eGórkiewicz Holger eBierhoff Marcin eWawrzyniak Artur K Janusz Birgit eLiss Witold eKonopka Günther eSchütz Leszek eKaczmarek Rosanna eParlato Rosanna eParlato Rosanna eParlato Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons Frontiers in Cellular Neuroscience Hippocampus Neurogenesis learning and memory rRNA mTOR nucleolus |
| title | Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons |
| title_full | Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons |
| title_fullStr | Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons |
| title_full_unstemmed | Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons |
| title_short | Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons |
| title_sort | impaired rrna synthesis triggers homeostatic responses in hippocampal neurons |
| topic | Hippocampus Neurogenesis learning and memory rRNA mTOR nucleolus |
| url | http://journal.frontiersin.org/Journal/10.3389/fncel.2013.00207/full |
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