Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice
Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice
复制标题
DOI：
10.1093/hmg/ddg046
复制
发表时间：
2003-03-01
影响因子：
3.5
通讯作者：
MacDonald, ME
中科院分区：
文献类型：
--
作者：
Gines, S;Seong, IS;MacDonald, ME
基因转录和线粒体功能的缺陷与导致亨廷顿病（HD）纹状体神经元丢失的主要疾病过程有关。在这里，我们已经使用精确的遗传HD小鼠和纹状体细胞模型，以调查的假设，减少cAMP反应元件（CRE）介导的基因转录可能反映受损的能量代谢。我们发现，减少CRE信号在Hdh（Q111）纹状体，监测脑源性神经营养因子和磷酸化CRE结合蛋白（CREB），早包涵体形成。此外，cAMP水平在Hdh（Q111）纹状体下降，从早期（10周），和cAMP显着减少，在HD死后的脑和淋巴母细胞，证明在man. Reduced慢性赤字在培养的STHdh（Q111）纹状体细胞的CREB信号与胞质CREB结合蛋白，反映减少cAMP合成。此外，突变细胞表现出线粒体呼吸链损伤，证明ATP和ATP/ADP比值下降，受损的MTT转化和3-硝基丙酸的敏感性增加。因此，我们的研究结果强烈表明，受损的ATP合成和减少cAMP水平放大早期HD疾病级联反应，通过减少CRE-regulated基因转录和改变能量依赖的过程中必不可少的神经元细胞的生存。
Defects in gene transcription and mitochondrial function have been implicated in the dominant disease process that leads to the loss of striatal neurons in Huntington's disease (HD). Here we have used precise genetic HD mouse and striatal cell models to investigate the hypothesis that decreased cAMP responsive element (CRE)-mediated gene transcription may reflect impaired energy metabolism. We found that reduced CRE-signaling in Hdh(Q111) striatum, monitored by brain derived neurotrophic factor and phospho-CRE binding protein (CREB), predated inclusion formation. Furthermore, cAMP levels in Hdh(Q111) striatum declined from an early age (10 weeks), and cAMP was significantly decreased in HD postmortem brain and lymphoblastoid cells, attesting to a chronic deficit in man. Reduced CRE-signaling in cultured STHdh(Q111) striatal cells was associated with cytosolic CREB binding protein that mirrored diminished cAMP synthesis. Moreover, mutant cells exhibited mitochondrial respiratory chain impairment, evidenced by decreased ATP and ATP/ADP ratio, impaired MTT conversion and heightened sensitivity to 3-nitropropionic acid. Thus, our findings strongly suggest that impaired ATP synthesis and diminished cAMP levels amplify the early HD disease cascade by decreasing CRE-regulated gene transcription and altering energy dependent processes essential to neuronal cell survival.