Integration of the deacetylase SIRT1 in the response to nucleolar stress: metabolic implications for neurodegenerative diseases
- 1Institute of Pharmacology, Polish Academy of Sciences, Poland
- 2University of Ulm, Germany
- 3Institute of Anatomy and Cell Biology, University of Heidelberg, Germany
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 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, and 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.
Keywords: Sirtuin 1 (SIRT1), Oxidative Stress, nucleolus, rRNA, p53, neuronal homeostasis, Neurodegenenerative diseases
Received: 28 Jan 2019;
Accepted: 09 Apr 2019.
Edited by:Daniela De Zio, Danish Cancer Society, Denmark
Reviewed by:Hee-Dae Kim, College of Medicine Phoenix, University of Arizona, United States
Dorthe H. Larsen, Danish Cancer Society, Denmark
Copyright: © 2019 Kreiner, Soenmez, Liss and Parlato. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Rosanna Parlato, University of Ulm, Ulm, 89081, Baden-Wurttemberg, Germany, email@example.com