PMID- 29289683 OWN - NLM STAT- MEDLINE DCOM- 20190131 LR - 20200629 IS - 1095-9327 (Electronic) IS - 1044-7431 (Linking) VI - 88 DP - 2018 Apr TI - Perturbations in the p53/miR-34a/SIRT1 pathway in the R6/2 Huntington's disease model. PG - 118-129 LID - S1044-7431(17)30099-4 [pii] LID - 10.1016/j.mcn.2017.12.009 [doi] 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. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Reynolds, Regina Hertfelder AU - Reynolds RH AD - Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen N, Denmark. FAU - Petersen, Maria Hvidberg AU - Petersen MH AD - Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen N, Denmark. FAU - Willert, Cecilie Wennemoes AU - Willert CW AD - Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen N, Denmark. FAU - Heinrich, Marie AU - Heinrich M AD - Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen N, Denmark. FAU - Nymann, Nynne AU - Nymann N AD - Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen N, Denmark. FAU - Dall, Morten AU - Dall M AD - 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. FAU - Treebak, Jonas T AU - Treebak JT AD - 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. FAU - Bjorkqvist, Maria AU - Bjorkqvist M AD - Brain Disease Biomarker Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Centre, Lund University, 221 84 Lund, Sweden. FAU - Silahtaroglu, Asli AU - Silahtaroglu A AD - Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen N, Denmark. FAU - Hasholt, Lis AU - Hasholt L AD - Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen N, Denmark. FAU - Norremolle, Anne AU - Norremolle A AD - Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen N, Denmark. Electronic address: annenoe@sund.ku.dk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171228 PL - United States TA - Mol Cell Neurosci JT - Molecular and cellular neurosciences JID - 9100095 RN - 0 (MIRN34a microRNA, mouse) RN - 0 (MicroRNAs) RN - 0 (Trp53 protein, mouse) RN - 0 (Tumor Suppressor Protein p53) RN - EC 3.5.1.- (Sirt1 protein, mouse) RN - EC 3.5.1.- (Sirtuin 1) SB - IM MH - Animals MH - Apoptosis/physiology MH - Cell Line MH - Disease Models, Animal MH - Huntington Disease/*genetics/metabolism MH - Mice, Transgenic MH - MicroRNAs/*genetics MH - Signal Transduction MH - Sirtuin 1/*genetics/metabolism MH - Tumor Suppressor Protein p53/*genetics/metabolism MH - Up-Regulation OTO - NOTNLM OT - Huntington's disease OT - SIRT1 OT - miR-34a OT - p53 EDAT- 2018/01/01 06:00 MHDA- 2019/02/01 06:00 CRDT- 2018/01/01 06:00 PHST- 2017/03/27 00:00 [received] PHST- 2017/12/21 00:00 [revised] PHST- 2017/12/27 00:00 [accepted] PHST- 2018/01/01 06:00 [pubmed] PHST- 2019/02/01 06:00 [medline] PHST- 2018/01/01 06:00 [entrez] AID - S1044-7431(17)30099-4 [pii] AID - 10.1016/j.mcn.2017.12.009 [doi] PST - ppublish SO - Mol Cell Neurosci. 2018 Apr;88:118-129. doi: 10.1016/j.mcn.2017.12.009. Epub 2017 Dec 28.