Transcriptional disturbance and Neurodegeneration.

通过使用同基因稳定的可诱导细胞系，我们发现聚谷氨酰胺拉伸在其早期阶段抑制了Cre依赖的转录。然而，在聚谷氨酰胺拉伸长度不同的不同细胞系中，它们的抑制效果并没有显着差异。此外，团聚体的存在不影响其抑制作用。综上所述，Cre介导的转录抑制不是聚谷氨酰胺病的致病因素。通过使用这些细胞系，我们发现扩张的聚谷氨酰胺以长度依赖的方式滞留在细胞内，特别是细胞核中。UPS是降解细胞中未折叠蛋白质的主要系统之一，在这些细胞系中没有受到抑制。其他神经退行性疾病，早发性共济失调伴眼球运动性失用和低蛋白血症(EAOH/AOA1)是由aptX基因突变引起的。我们发现aptX与X射线修复交叉互补第一组蛋白结合，这是单链DNA断裂修复(SSBR)中碱基切除修复(BER)机制的支架蛋白，并与聚(ADP-核糖)聚合酶形成复合体。这些发现支持aptX可能在SSBR系统中发挥重要作用的观点。

By using isogenic stable inducible cell lines, we showed the polyglutamine stretch suppressed the CRE dependent transcription in their early stage. However their repressive effects were not so dramatically different in different cell lines which have different length of polyglutamine stretch. Furthermore its repressive effect is not affected the existence of aggregate formation. Taken together CRE mediated transcriptional repression was not a pathogenic for polyglutamine disease. By using these cell lines, we showed the expanded polyglutamine stretch retained in cell, speciously in nucleus by length dependent manner. The UPS, one of the main systems to degradate unfolded proteins in cells, was not suppressed in these cell lines. Therefore we speculated that polyglutamine stretch itself has resistance to degradation, thus accumulate in nucleus.The other neurodegenerative disorders, early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH/AOA1) is caused by mutation of APTX. We show the APTX binds to X-ray repair cross-complementing group 1 protein, which is the scaffold protein for base excision repair (BER) machinery in single strand DNA break repair (SSBR), and made complex with poly (ADP-ribose) polymerase. These findings support the idea that APTX might take an important role in SSBR system.