Basic Research for Development of Novel Therapeutics of Polyglutamine Diseases through Transcriptional Regulation

在这项研究中，我们通过转录组和蛋白质组分析来研究基因表达谱的变化。我们已经发现了多个候选基因，它们在受PolyQ病影响的特定类型的神经元中表达变化。其中，我们目前关注的是HSP70，它的表达被突变的Huntingtin表达显著上调，而不是被突变的ataxin-1上调。其他类型的神经元如颗粒细胞或皮质神经元未见明显增加。我们进一步分析了转录上调的分子机制，发现HSF1是一个著名的影响热休克蛋白表达的转录因子，它不参与突变的HTT的上调。相反，我们发现另一种转录因子P53在HSP70表达的调节中起关键作用。我们计划在未来利用这一结果开发新的疗法。

In this study, we investigated changes of gene expression profiles by transcriptome and proteome analyses. We have found multiple candidate genes whose expression changes in specific types of neurons affected in polyQ diseases. Among them, we currently focus on hsp70 whose expression was dramatically up-regulated instriatal neurons by mutant huntingtin expression but not by mutant ataxin-1. The remarkable increase was not observed in other types of neurons such as granule cells or cortical neurons. We further analyzed molecular mechanisms underlying transcriptional upregulation, and found that HSF1, a famous transcription factor affecting expression of heat shock proteins, is not involve in the upregulation by mutant htt. Instead, we found another transcription factor p53 is critically involved in the regulation of hsp70 expression.We plan to use the result for developing nove therapeutics in the future.