Transducer of regulated CREB-binding proteins (TORCs) transcription and function is impaired in Huntingtons disease
Transducer of regulated CREB-binding proteins (TORCs) transcription and function is impaired in Huntingtons disease
复制标题
DOI：
10.1093/hmg/dds178
复制
发表时间：
2012-08-01
影响因子：
3.5
通讯作者：
Beal, M. Flint
中科院分区：
文献类型：
--
作者：
Chaturvedi, Rajnish Kumar;Hennessey, Thomas;Beal, M. Flint
亨廷顿病（HD）是一种无法治愈的神经系统疾病，由亨廷顿蛋白（Htt）中谷氨酰胺重复扩增异常引起。在本研究中，我们研究了受调节的cAMP反应元件结合（CREB）蛋白活性（TORCs）转导器在HD中的作用，因为TORCs在转录共调节剂过氧化物酶体增殖激活受体γ共激活因子1 （PGC-1）的表达中起重要作用，而PGC-1的表达在HD中受损。我们发现，在表达突变Htt的STHdhQ111细胞、NLS-N171-82Q、R6/2和HdhQ111 HD转基因小鼠纹状体以及HD患者死后纹状体组织中，TORC1的表达水平显著降低。野生型（WT）和Htt纹状体细胞中TORC1过表达增加了CREB mRNA和蛋白水平、PGC-1启动子活性、PGC-1、NRF-1、Tfam和CytC基因mRNA表达、线粒体DNA含量、线粒体活性和线粒体膜电位。TORC1过表达还增加纹状体细胞对3-硝基丙酸（3-NP）介导的毒性的抗性。在培养的WT和突变的Htt纹状体细胞中，小发夹rna介导的TORC1敲低导致PGC-1表达降低，并增加对3- np诱导的毒性的易感性。PGC-1过表达部分阻止了TORC1敲低介导的Htt纹状体细胞对3-NP的易感性增加。NLS-N171-82Q HD转基因小鼠纹状体特异性敲低TORC1可诱导神经变性。最后，在Htt纹状体细胞中，敲低Htt可阻止TORC1和CREB的转录抑制。这些发现表明，TORC1的表达和功能受损，导致PGC-1的减少，在HD的线粒体功能障碍中起重要作用。
Huntingtons disease (HD) is an incurable neurological disorder caused by an abnormal glutamine repeat expansion in the huntingtin (Htt) protein. In the present studies, we investigated the role of Transducers of Regulated cAMP response element-binding (CREB) protein activity (TORCs) in HD, since TORCs play an important role in the expression of the transcriptional co-regulator peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), whose expression is impaired in HD. We found significantly decreased TORC1 expression levels in STHdhQ111 cells expressing mutant Htt, in the striatum of NLS-N171-82Q, R6/2 and HdhQ111 HD transgenic mice and in postmortem striatal tissue from HD patients. TORC1 overexpression in wild-type (WT) and Htt striatal cells increased CREB mRNA and protein levels, PGC-1 promoter activity, mRNA expression of the PGC-1, NRF-1, Tfam and CytC genes, mitochondrial DNA content, mitochondrial activity and mitochondrial membrane potential. TORC1 overexpression also increased the resistance of striatal cells to 3-nitropropionic (3-NP) acid-mediated toxicity. In cultured WT and mutant Htt striatal cells, small hairpin RNA-mediated TORC1 knockdown resulted in decreased PGC-1 expression and increased susceptibility to 3-NP-induced toxicity. Overexpression of PGC-1 partially prevented TORC1 knockdown-mediated increased susceptibility of Htt striatal cells to 3-NP. Specific knockdown of TORC1 in the striatum of NLS-N171-82Q HD transgenic mice induced neurodegeneration. Lastly, knockdown of Htt prevents transcriptional repression of TORC1 and CREB in Htt striatal cells. These findings show that impaired expression and function of TORC1, which results in a reduction in PGC-1, plays an important role in mitochondrial dysfunction in HD.