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Perturbations in the p53/miR-34a/SIRT1 pathway in the R6/2 Huntington's disease model
Regina Hertfelder Reynolds1, Maria Hvidberg Petersen1, Cecilie Wennemoes Willert1
1Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
Abstract:
The three factors, p53, the microRNA-34 family and Sirtuin 1 (SIRT1), interact in a positive feedback loop involved in cell cycle progression, cellular senescence and apoptosis. Each factor in this triad has roles in metabolic regulation, maintenance of mitochondrial function, and regulation of brain-derived neurotrophic factor (BDNF). Thus, this regulatory network holds potential importance for the pathophysiology of Huntington's disease (HD), an inherited neurodegenerative disorder in which both mitochondrial dysfunction and impaired neurotrophic signalling are observed. We investigated expression of the three members of this regulatory triad in the R6/2 HD mouse model. Compared to wild-type littermates, we found decreased levels of miR-34a-5p, increased SIRT1 mRNA and protein levels, and increased levels of p53 protein in brain tissue from R6/2 mice. The upregulation of SIRT1 did not appear to lead to an increased activity of the enzyme, as based on measures of p53 acetylation. In other words, the observed changes did not reflect the known interactions between these factors, indicating a general perturbation of the p53, miR-34a and SIRT1 pathway in HD. This is the first study investigating the entire triad during disease progression in an HD model. Given the importance of these three factors alone and within the triad, our results indicate that outside factors are regulating - or dysregulating - this pathway in HD.
Insights
Huntington's disease (HD) disrupts the p53, microRNA-34, and Sirtuin 1 (SIRT1) pathway. This study found altered expression of these key factors in an HD mouse model, suggesting external dysregulation.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The p53, microRNA-34 family, and Sirtuin 1 (SIRT1) form a regulatory network crucial for cellular processes.
- This network influences metabolism, mitochondrial function, and neurotrophic signaling, making it relevant to neurodegenerative diseases like Huntington's disease (HD).
- Mitochondrial dysfunction and impaired neurotrophic signaling are hallmarks of HD.
Purpose of the Study:
- To investigate the expression and interaction of the p53, miR-34a, and SIRT1 triad in a mouse model of Huntington's disease (HD).
- To determine if the known positive feedback loop between these factors is maintained in the context of HD.
- To explore potential dysregulation of this pathway during HD progression.
Main Methods:
- Utilized the R6/2 mouse model of Huntington's disease (HD).
- Analyzed brain tissue from R6/2 mice and wild-type littermates.
- Quantified expression levels of p53, miR-34a-5p, and SIRT1 (mRNA and protein).
- Assessed SIRT1 activity indirectly via p53 acetylation levels.
Main Results:
- Decreased levels of miR-34a-5p were observed in R6/2 mice.
- Increased SIRT1 mRNA and protein levels were found in R6/2 mice.
- Elevated p53 protein levels were detected in R6/2 mouse brain tissue.
- SIRT1 upregulation did not correlate with increased enzyme activity, as indicated by p53 acetylation levels.
- Observed changes suggest a perturbation of the p53-miR-34a-SIRT1 pathway in HD, deviating from expected interactions.
Conclusions:
- This is the first study to examine the entire p53, miR-34a, and SIRT1 triad throughout HD progression in a mouse model.
- The findings indicate a significant dysregulation of this critical pathway in Huntington's disease.
- External factors appear to be influencing or disrupting the p53-miR-34a-SIRT1 regulatory network in HD.