Pathological roles of dentatorabral-pallidoluysian atrophy (DRPLA) protein in DRPLA brain tissue

近10 ~ 20年来，日本2型糖尿病患者的数量急剧上升，至少部分原因是饮食习惯的西化和久坐的生活方式。以前，人们认为，在日本人中，与胰岛素分泌受损的发病机制有关的基因比与胰岛素抵抗的发展有关的基因更重要。然而，最近的观察表明，那些负责胰岛素抵抗或肥胖发展的基因同样重要。我们从无关的日本2型糖尿病患者中提取基因组DNA。我们研究了多态性的关联，这些多态性已被报道存在于2型糖尿病发展的候选基因附近。我们还调查了这些遗传变异与日本2型糖尿病的可能关联。我们没有发现这些基因变异与2型糖尿病有显著的关联。 关于我们 睾丸谷氨酰胺重复序列（Polyglutamine-repeat，Polyglutaminase）疾病是一组遗传性神经退行性疾病，由负责基因产物中的谷氨酰胺重复序列扩增引起。该组包括亨廷顿病（HD）和齿状核红核苍白球路易氏体萎缩（DRPLA）。在HD和DRPLA患者的脑组织中发现了与基因产物呈免疫反应性的神经元核内和细胞质包涵体。携带扩展的谷氨酰胺重复序列的基因产物的聚集似乎是谷氨酰胺重复序列疾病的主要病理机制，尽管聚集和神经元变性之间的精确关系尚不清楚。我们对DRPLA的研究表明，根据非还原条件下电泳获得的免疫印迹数据，DRPLA患者的脑组织中发生了涉及DRPLA基因产物（DRPLA蛋白）的异常蛋白复合物形成引起的几种疾病过程。第一个过程是由于DRPLA蛋白分子之间异常强的键合而形成大的复合物。第二种是DRPLA蛋白复合物的病理性泛素化。最近，使用抗磷酸丝氨酸抗体和分离的DRPLA蛋白复合物的酶促去磷酸化的免疫印迹研究使我们能够证明DRPLA蛋白复合物在DRPLA脑组织中异常磷酸化作为第三种疾病过程。少

The number of patients afflicted with type 2 diabetes has risen sharply in Japan these ten to twenty years, at least partly because of a westernization of eating habit and of a sedentary life style. Previously, it was thought that genes involved in the pathogenesis of impaired insulin secretion are more important than those involved in the development of insulin resistance in Japanese. Recent observations, however, suggest that those genes responsible for the development of insulin resistance or obesity are as important. We extracted genomic DNA from unrelated Japanese patients with type 2 diabetes mellitus. We investigated for an association of polymorphisms, which have been reported to be present near candidate genes for the development of type 2 diabetes mellitus. We also investigated for a possible association of those genetic variants, identified by us, with type 2 diabetes mellitus in Japanese. We could not find a significant association of the genetic variants, with type 2 diabe … More tes mellitus. Increased number of DNA samples seems to be necessary to identify susceptible genes for the development of diabetes mellitus.Glutamine-repeat (Polyglutamine) diseases are a group of hereditary neurodegenerative disorders caused by expansion of a glutamine repeat in responsible gene products. This group includes Huntington s disease (HD) and dentatorubral-pallidoluysian atrophy (DRPLA). Neuronal intranuclear and cytoplasmic inclusions showing immunoreactivity with the gene product are found in brain tissues of patients with HD and DRPLA. Aggregation of the gene products that carry an expanded glutamine repeat seems to be a primary pathological mechanism in glutamine-repeat diseases, although the precise relationship between aggregation and neuronal degeneration is unclear. Our studies of DRPLA demonstrated that several disease processes arising from abnormal protein complex formation involving the DRPLA gene product (DRPLA protein) occur in brain tissues of patients with DRPLA based on immunoblotting data obtained by electrophoresis under non-reducing conditions. The first process is large complex formation due to abnormally strong bonding between DRPLA protein molecules. The second is pathological ubiquitination of the DRPLA protein complex. Immunoblotting studies using anti-phosphoserine antibody and enzymatic dephosphorylation of isolated DRPLA protein complexes recently enabled us to demonstrate that DRPLA protein complexes are aberrantly phosphorylated in DRPLA brain tissues as the third disease process. Less