Analysis of pathological cascade in CAG repeat disease

近年来，以三核苷酸重复扩增为特征的疾病种类迅速增加。到目前为止，有以下疾病被报道由CAG重复扩增引起：脊髓和球性肌萎缩症（SBMA）、亨廷顿病、SCA1、齿状神经-白球性萎缩症（DRPLA）、MJD和SCA2。扩增的CAG重复序列位于这些疾病患者的基因编码区域内。我们发现异常基因产物实际上在HD和DRPLA中被翻译，这表明扩大的聚谷氨酰胺拉伸在这些疾病的病理机制中起作用。在这项研究中，我们通过寻找与基因产物相关的分子来研究基因产物的功能。得到了以下结果：1)鉴定了DRPLA基因产物在淋巴母细胞样细胞中的表达；2)通过双向凝胶电泳分析DRPLA基因产物，发现了DRPLA蛋白磷酸化的同工型。3)利用双杂交系统获得了两个与DRPLA基因产物结合的蛋白。4)鉴定MJD基因产物并报道其表达。5)我们发现了HD基因产物与微管的关联。

Recently, the list of diseases characterized by trinucleotide repeat expansions has grown rapidly. So far, the following diseases have been reported to be caused by CAG repeat expansion : spinal and bulbar muscular atrophy (SBMA), Huntington's diseases, SCA1, dentatorubral-pallidoluysian atrophy (DRPLA), MJD,and SCA2. The expanded CAG repeat is located within the coding regions of the genes of patients with these diseases. We have revealed that the abnormal gene product is actually translated in HD,and DRPLA,suggesting that the expanded polyglutamine stretch plays a role in the pathomechanism of these diseases.In this study, we have investigated the function of gene products by searching the related molecules with the gene product. The following results were obtained.1) We identified the DRPLA gene product expression in lymphoblastoid cells2) Analyzing DRPLA gene products with the two-dimensional gel electrophoresis, we found the isoforms of DRPLA proteins which are phosphorylated.3) We obtained two binding proteins with DRPLA gene product using two-hybrid system.4) We identified the MJD gene products and reported their expression.5) We showed the association of HD gene products with microtubules.