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.

p53，microRNA-34家族和Sirtuin 1（SIRT1）这三个因子在涉及细胞周期进程，细胞衰老和凋亡的正反馈回路中相互作用。该三联体中的每个因子在代谢调节，线粒体功能维持和脑源性神经营养因子（BDNF）调节中均具有作用。因此，该调节网络对于亨廷顿氏病（HD）的病理生理学具有潜在的重要性，亨廷顿氏病是一种遗传性神经退行性疾病，其中观察到了线粒体功能障碍和神经营养信号受损。我们研究了在R6 / 2 HD小鼠模型中该调节三联体的三个成员的表达。与野生型同窝仔相比，我们发现miR-34a-5p水平降低，SIRT1 mRNA和蛋白水平升高，R6 / 2小鼠脑组织中p53蛋白的水平升高。基于p53乙酰化的测量，SIRT1的上调似乎并未导致酶活性的增加。换句话说，观察到的变化并未反映这些因素之间的已知相互作用，这表明HD中p53，miR-34a和SIRT1途径普遍受到干扰。这是第一项研究HD模型疾病进展过程中整个三联征的研究。考虑到这三个因素本身的重要性以及在三合会内部的重要性，我们的结果表明，外部因素正在调节（或失调）HD的这一途径。观察到的变化并未反映这些因素之间的已知相互作用，这表明HD中p53，miR-34a和SIRT1途径普遍受到干扰。这是第一项研究HD模型疾病进展过程中整个三联征的研究。考虑到这三个因素本身的重要性以及在三合会内部的重要性，我们的结果表明，外部因素正在调节（或失调）HD的这一途径。观察到的变化并未反映这些因素之间的已知相互作用，这表明HD中p53，miR-34a和SIRT1途径普遍受到干扰。这是第一项研究HD模型疾病进展过程中整个三联征的研究。考虑到这三个因素本身的重要性以及在三合会内部的重要性，我们的结果表明，外部因素正在调节（或失调）HD的这一途径。