p53 increases caspase-6 expression and activation in muscle tissue expressing mutant huntingtin
p53 increases caspase-6 expression and activation in muscle tissue expressing mutant huntingtin
复制标题
DOI：
10.1093/hmg/ddt458
复制
发表时间：
2014-02-01
影响因子：
3.5
通讯作者：
Hayden, Michael R.
中科院分区：
文献类型：
--
作者：
Ehrnhoefer, Dagmar E.;Skotte, Niels H.;Hayden, Michael R.
在症状前和亨廷顿病(HD)患者中，纹状体中caspase-6的激活是该病发病机制中的早期事件。然而，关于caspase-6在中枢神经系统(CNS)外的作用以及caspase激活是否在外周表型(如HD中观察到的肌肉萎缩)中发挥作用，人们知之甚少。我们评估了HD患者的骨骼肌组织和具有良好特征的HD小鼠模型。Caspase-6特异性底物lamin A在HD患者的骨骼肌和两种不同HD小鼠模型的肌肉组织中的裂解显著增加。P53是caspase-6的转录激活因子，在表达突变的亨廷顿蛋白的神经细胞和组织中表达上调。P53的激活导致caspase-6mRNA水平、caspase-6活性和层蛋白A的裂解显著增加。我们使用来自YAC128小鼠的小鼠胚胎成纤维细胞(MEF)，我们发现这种caspase-6活性的增加可以被P53转录活性的抑制剂Pifithin-Alpha(PIFα)缓解，但不是通过抑制P53‘S的线粒体促凋亡功能来实现的。值得注意的是，在表达突变型Huntingtin(Htt)的神经元和外周来源的细胞和组织中，P53介导的caspase-6表达和激活的增加被加剧。这些发现表明，突变的Htt蛋白的存在增强了P53的活性，降低了凋亡阈值，从而激活了caspase-6。此外，这些结果表明，这一通路在HD患者的中枢神经系统内外都被激活，可能与中枢神经系统神经元的丢失和肌肉萎缩有关。
Activation of caspase-6 in the striatum of both presymptomatic and affected persons with Huntington's disease (HD) is an early event in the disease pathogenesis. However, little is known about the role of caspase-6 outside the central nervous system(CNS) and whether caspase activation might play a role in the peripheral phenotypes, such as muscle wasting observed in HD. We assessed skeletal muscle tissue from HD patients and well-characterized mouse models of HD. Cleavage of the caspase-6 specific substrate lamin A is significantly increased in skeletal muscle obtained from HD patients as well as in muscle tissues from two different HD mouse models. p53, a transcriptional activator of caspase-6, is upregulated in neuronal cells and tissues expressing mutant huntingtin. Activation of p53 leads to a dramatic increase in levels of caspase-6 mRNA, caspase-6 activity and cleavage of lamin A. Using mouse embryonic fibroblasts (MEFs) from YAC128 mice, we show that this increase in caspase-6 activity can be mitigated by pifithrin-alpha (pif alpha), an inhibitor of p53 transcriptional activity, but not through the inhibition of p53's mitochondrial pro-apoptotic function. Remarkably, the p53-mediated increase in caspase-6 expression and activation is exacerbated in cells and tissues of both neuronal and peripheral origin expressing mutant huntingtin(Htt). These findings suggest that the presence of the mutant Htt protein enhances p53 activity and lowers the apoptotic threshold, which activates caspase-6. Furthermore, these results suggest that this pathway is activated both within and outside the CNS in HD and may contribute to both loss of CNS neurons and muscle atrophy.