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

Reynolds, Regina Hertfelder; Petersen, Maria Hvidberg; Willert, Cecilie Wennemoes; Heinrich, Marie; Nymann, Nynne; Dall, Morten; Treebak, Jonas T.; Björkqvist, Maria LU ; Silahtaroglu, Asli and Hasholt, Lis, et al. (2018) In Molecular and Cellular Neuroscience 88. p.118-129
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... (More)

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.

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publication status
published
subject
keywords
Huntington's disease, miR-34a, p53, SIRT1
in
Molecular and Cellular Neuroscience
volume
88
pages
12 pages
publisher
Elsevier
external identifiers
  • scopus:85041479987
ISSN
1044-7431
DOI
10.1016/j.mcn.2017.12.009
language
English
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yes
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b036e96d-bc74-4687-b79c-f78a00436edf
date added to LUP
2018-02-20 10:43:57
date last changed
2018-10-29 04:10:08
@article{b036e96d-bc74-4687-b79c-f78a00436edf,
  abstract     = {<p>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.</p>},
  author       = {Reynolds, Regina Hertfelder and Petersen, Maria Hvidberg and Willert, Cecilie Wennemoes and Heinrich, Marie and Nymann, Nynne and Dall, Morten and Treebak, Jonas T. and Björkqvist, Maria and Silahtaroglu, Asli and Hasholt, Lis and Nørremølle, Anne},
  issn         = {1044-7431},
  keyword      = {Huntington's disease,miR-34a,p53,SIRT1},
  language     = {eng},
  month        = {04},
  pages        = {118--129},
  publisher    = {Elsevier},
  series       = {Molecular and Cellular Neuroscience},
  title        = {Perturbations in the p53/miR-34a/SIRT1 pathway in the R6/2 Huntington's disease model},
  url          = {http://dx.doi.org/10.1016/j.mcn.2017.12.009},
  volume       = {88},
  year         = {2018},
}