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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Regina Hertfelder Reynolds
  • Maria Hvidberg Petersen
  • Cecilie Wennemoes Willert
  • Marie Heinrich
  • Nynne Nymann
  • Morten Dall
  • Jonas T. Treebak
  • Maria Björkqvist
  • Asli Silahtaroglu
  • Lis Hasholt
  • Anne Nørremølle
Enheter & grupper
Externa organisationer
  • University of Copenhagen
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Neurologi

Nyckelord

Originalspråkengelska
Sidor (från-till)118-129
Antal sidor12
TidskriftMolecular and Cellular Neuroscience
Volym88
StatusPublished - 2018 apr 1
PublikationskategoriForskning
Peer review utfördJa