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Mol Cell Neurosci. 2018 Apr;88:118-129. doi: 10.1016/j.mcn.2017.12.009. Epub 2017 Dec 28.

Perturbations in the p53/miR-34a/SIRT1 pathway in the R6/2 Huntington's disease model.

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Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
Brain Disease Biomarker Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Centre, Lund University, 221 84 Lund, Sweden.
Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen N, Denmark. Electronic address:


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.


Huntington's disease; SIRT1; miR-34a; p53


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