TY - JOUR

T1 - Perturbations in the p53/miR-34a/SIRT1 pathway in the R6/2 Huntington's disease model

AU - Reynolds, Regina Hertfelder

AU - Petersen, Maria Hvidberg

AU - Willert, Cecilie Wennemoes

AU - Heinrich, Marie

AU - Nymann, Nynne

AU - Dall, Morten

AU - Treebak, Jonas T.

AU - Björkqvist, Maria

AU - Silahtaroglu, Asli

AU - Hasholt, Lis

AU - Nørremølle, Anne

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1016/j.mcn.2017.12.009

DO - 10.1016/j.mcn.2017.12.009

M3 - Journal article

C2 - 29289683

VL - 88

SP - 118

EP - 129

JO - Molecular and Cellular Neurosciences

JF - Molecular and Cellular Neurosciences

SN - 1044-7431

ER -