Mutant Huntingtin reduces HSP70 expression through the sequestration of NF‐Y transcription factor
Mutant Huntingtin reduces HSP70 expression through the sequestration of NF‐Y transcription factor
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DOI：
10.1038/emboj.2008.23
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发表时间：
2008-03
期刊：
影响因子：
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通讯作者：
T. Yamanaka;Haruko Miyazaki;F. Oyama;M. Kurosawa;Chika Washizu;H. Doi;N. Nukina
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文献类型：
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作者：
T. Yamanaka;Haruko Miyazaki;F. Oyama;M. Kurosawa;Chika Washizu;H. Doi;N. Nukina
在亨廷顿病(HD)中，突变的亨廷顿蛋白含有扩展的聚谷氨酰胺延伸部分，在神经元中形成核聚集体。一些转录因子与突变的亨廷顿蛋白的相互作用，以及HD模型中许多基因表达的改变，暗示转录失调参与了HD的病理过程。然而，确切的机制仍然不清楚。在这里，我们证明了突变的Huntingtin聚集体在体外和HD模型小鼠脑中与NF-Y转录因子的成分相互作用。使用HD模型小鼠脑裂解物进行的电泳迁移率改变分析显示，NF-Y与HSP70启动子区域的结合减少，HSP70是NF-Y靶标之一。RT-PCR分析显示，这些脑组织中HSP70的表达减少。我们进一步阐明了核因子-Y对培养神经元中HSP70转录的重要性。这些数据表明，突变的Huntingtin隔离了NF-Y，导致HD模型小鼠脑内HSP70基因表达减少。由于HSP70在HD病理过程中的抑制作用已在多个HD模型中显示，因此，NF-Y可能是突变的Huntingtin的一个重要靶点。
In Huntington's disease (HD), mutant Huntingtin, which contains expanded polyglutamine stretches, forms nuclear aggregates in neurons. The interactions of several transcriptional factors with mutant Huntingtin, as well as altered expression of many genes in HD models, imply the involvement of transcriptional dysregulation in the HD pathological process. The precise mechanism remains obscure, however. Here, we show that mutant Huntingtin aggregates interact with the components of the NF‐Y transcriptional factorin vitroand in HD model mouse brain. An electrophoretic mobility shift assay using HD model mouse brain lysates showed reduction in NF‐Y binding to the promoter region of HSP70, one of the NF‐Y targets. RT–PCR analysis revealed reduced HSP70 expression in these brains. We further clarified the importance of NF‐Y for HSP70 transcription in cultured neurons. These data indicate that mutant Huntingtin sequesters NF‐Y, leading to the reduction of HSP70 gene expression in HD model mice brain. Because suppressive roles of HSP70 on the HD pathological process have been shown in several HD models, NF‐Y could be an important target of mutant Huntingtin.