Integration of the Deacetylase SIRT1 in the Response to Nucleolar Stress: Metabolic Implications for Neurodegenerative Diseases
Understanding underlying mechanisms of neurodegenerative diseases is fundamental to develop effective therapeutic intervention. Yet they remain largely elusive, but metabolic, and transcriptional dysregulation are common events. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-depende...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-04-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnmol.2019.00106/full |
| _version_ | 1818924510203609088 |
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| author | Grzegorz Kreiner Aynur Sönmez Birgit Liss Birgit Liss Rosanna Parlato Rosanna Parlato |
| author_facet | Grzegorz Kreiner Aynur Sönmez Birgit Liss Birgit Liss Rosanna Parlato Rosanna Parlato |
| author_sort | Grzegorz Kreiner |
| collection | DOAJ |
| description | Understanding underlying mechanisms of neurodegenerative diseases is fundamental to develop effective therapeutic intervention. Yet they remain largely elusive, but metabolic, and transcriptional dysregulation are common events. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase, regulating transcription, and critical for the cellular adaptations to metabolic stress. SIRT1 regulates the transcription of ribosomal RNA (rRNA), connecting the energetic state with cell growth and function. The activity of the transcription initiation factor-IA (TIF-IA) is important for the transcriptional regulation of ribosomal DNA (rDNA) genes in the nucleolus, and is also sensitive to changes in the cellular energetic state. Moreover, TIF-IA is responsive to nutrient-deprivation, neurotrophic stimulation, and oxidative stress. Hence, both SIRT1 and TIF-IA connect changes in cellular stress with transcriptional regulation and metabolic adaptation. Moreover, they finely tune the activity of the transcription factor p53, maintain mitochondrial function, and oxidative stress responses. Here we reviewed and discussed evidence that SIRT1 and TIF-IA are regulated by shared pathways and their activities preserve neuronal homeostasis in response to metabolic stressors. We provide evidence that loss of rDNA transcription due to altered TIF-IA function alters SIRT1 expression and propose a model of interdependent feedback mechanisms. An imbalance of this signaling might be a critical common event in neurodegenerative diseases. In conclusion, we provide a novel perspective for the prediction of the therapeutic benefits of the modulation of SIRT1- and nucleolar-dependent pathways in metabolic and neurodegenerative diseases. |
| first_indexed | 2024-12-20T02:26:28Z |
| format | Article |
| id | doaj.art-21cb8a82f19e4a05bc3a678e4494952a |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-20T02:26:28Z |
| publishDate | 2019-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-21cb8a82f19e4a05bc3a678e4494952a2022-12-21T19:56:41ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992019-04-011210.3389/fnmol.2019.00106450858Integration of the Deacetylase SIRT1 in the Response to Nucleolar Stress: Metabolic Implications for Neurodegenerative DiseasesGrzegorz Kreiner0Aynur Sönmez1Birgit Liss2Birgit Liss3Rosanna Parlato4Rosanna Parlato5Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Kraków, PolandInstitute of Applied Physiology, University of Ulm, Ulm, GermanyInstitute of Applied Physiology, University of Ulm, Ulm, GermanyNew College, Oxford University, Oxford, United KingdomInstitute of Applied Physiology, University of Ulm, Ulm, GermanyDepartment of Medical Cell Biology, Institute of Anatomy and Cell Biology, University of Heidelberg, Heidelberg, GermanyUnderstanding underlying mechanisms of neurodegenerative diseases is fundamental to develop effective therapeutic intervention. Yet they remain largely elusive, but metabolic, and transcriptional dysregulation are common events. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase, regulating transcription, and critical for the cellular adaptations to metabolic stress. SIRT1 regulates the transcription of ribosomal RNA (rRNA), connecting the energetic state with cell growth and function. The activity of the transcription initiation factor-IA (TIF-IA) is important for the transcriptional regulation of ribosomal DNA (rDNA) genes in the nucleolus, and is also sensitive to changes in the cellular energetic state. Moreover, TIF-IA is responsive to nutrient-deprivation, neurotrophic stimulation, and oxidative stress. Hence, both SIRT1 and TIF-IA connect changes in cellular stress with transcriptional regulation and metabolic adaptation. Moreover, they finely tune the activity of the transcription factor p53, maintain mitochondrial function, and oxidative stress responses. Here we reviewed and discussed evidence that SIRT1 and TIF-IA are regulated by shared pathways and their activities preserve neuronal homeostasis in response to metabolic stressors. We provide evidence that loss of rDNA transcription due to altered TIF-IA function alters SIRT1 expression and propose a model of interdependent feedback mechanisms. An imbalance of this signaling might be a critical common event in neurodegenerative diseases. In conclusion, we provide a novel perspective for the prediction of the therapeutic benefits of the modulation of SIRT1- and nucleolar-dependent pathways in metabolic and neurodegenerative diseases.https://www.frontiersin.org/article/10.3389/fnmol.2019.00106/fullsirtuinoxidative stressnucleolusrRNAp53neuronal homeostasis |
| spellingShingle | Grzegorz Kreiner Aynur Sönmez Birgit Liss Birgit Liss Rosanna Parlato Rosanna Parlato Integration of the Deacetylase SIRT1 in the Response to Nucleolar Stress: Metabolic Implications for Neurodegenerative Diseases Frontiers in Molecular Neuroscience sirtuin oxidative stress nucleolus rRNA p53 neuronal homeostasis |
| title | Integration of the Deacetylase SIRT1 in the Response to Nucleolar Stress: Metabolic Implications for Neurodegenerative Diseases |
| title_full | Integration of the Deacetylase SIRT1 in the Response to Nucleolar Stress: Metabolic Implications for Neurodegenerative Diseases |
| title_fullStr | Integration of the Deacetylase SIRT1 in the Response to Nucleolar Stress: Metabolic Implications for Neurodegenerative Diseases |
| title_full_unstemmed | Integration of the Deacetylase SIRT1 in the Response to Nucleolar Stress: Metabolic Implications for Neurodegenerative Diseases |
| title_short | Integration of the Deacetylase SIRT1 in the Response to Nucleolar Stress: Metabolic Implications for Neurodegenerative Diseases |
| title_sort | integration of the deacetylase sirt1 in the response to nucleolar stress metabolic implications for neurodegenerative diseases |
| topic | sirtuin oxidative stress nucleolus rRNA p53 neuronal homeostasis |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2019.00106/full |
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