Abstract
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.
Highlights
Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase responsive to metabolic fluctuations and involved in the regulation of a myriad of cellular processes including mitochondrial biogenesis, genomic stability, cellular senescence, and apoptosis (Palacios et al, 2010; Yuan et al, 2016)
Based on previous findings and original results, we propose a model of the circuitry that interconnects SIRT1 and ribosomal RNA (rRNA) synthesis with each other, with p53 function, and with signaling pathways regulating metabolic adaptation and neuronal survival
Given the central role of a dysfunctional nucleolus in neuronal homeostasis and its emerging dysregulation in neurodegenerative disorders, therapeutic approaches aiming at promoting SIRT1 activity will need to be tested for their impact on the function and integrity of the nucleolus and the restoration of nucleolardependent signaling
Summary
Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase responsive to metabolic fluctuations and involved in the regulation of a myriad of cellular processes including mitochondrial biogenesis, genomic stability, cellular senescence, and apoptosis (Palacios et al, 2010; Yuan et al, 2016). Expression and activity is important to understand the impact of restoring SIRT1, and nucleolar function, in neurodegenerative disorders To this end we took advantage of gene expression profiling data by GeneChip Mouse Genome 430A 2.0 array (Affymetrix, Santa Clara, CA, United States), obtained from conditional knock-out mice lacking TIF-IA in HD-relevant dopaminoceptive striatal neurons, indicated as TIF-IAD1RCre (Kreiner et al, 2013). These results indicate that inhibition of rDNA transcription and disruption of nucleolar integrity are accompanied by a decreased SIRT1 protein expression, suggesting that there is a crosstalk between SIRT1 protein and nucleolar function Based on these and previous findings we propose a model in which SIRT1- and nucleolar-dependent signaling pathways are integrated for the regulation of p53 acetylation and activity upon induction of nucleolar stress (Figure 2). The understanding of the cell-specific link between nucleolar stress and SIRT1 promises a more precise interpretation and prediction of therapeutic benefits
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
