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

近十到二十年来，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不动的生活方式。此前，在日本，人们认为参与胰岛素分泌受损发病机制的基因比参与胰岛素抵抗发展的基因更重要。然而，最近的观察表明，那些导致胰岛素抵抗或肥胖的基因也同样重要。我们提取了无血缘关系的日本2型糖尿病患者的基因组DNA。我们调查了多态之间的关联，据报道，这些多态存在于2型糖尿病发生的候选基因附近。我们还调查了我们确定的这些基因变异与日本人2型糖尿病的可能联系。我们没有找到与2型DIABE…有显著关联的遗传变异更多的血栓形成。增加DNA样本的数量似乎是必要的，以确定糖尿病的易感基因。谷氨酰胺重复(多谷氨酰胺)疾病是一组遗传性神经退行性疾病，由谷氨酰胺重复序列在相关基因产物中的扩增引起。本组包括亨廷顿S病(HD)和齿状核苍白球萎缩症(DRPLA)。在HD和DRLA患者的脑组织中发现了与该基因产物呈免疫反应的神经元核内和胞浆内包涵体。携带扩大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，尽管聚集与神经元变性之间的确切关系尚不清楚。我们对DRLA的研究表明，在非还原条件下通过电泳获得的免疫印迹数据表明，在DRLA患者的脑组织中发生了几种疾病过程，这些疾病是由于涉及DRLA基因产物的异常蛋白质复合体(DRLA蛋白)而引起的。第一个过程是由于DRPLA蛋白分子之间异常强烈的结合而形成的大型复杂结构。第二个是DRPLA蛋白复合体的病理性泛素化。最近，利用抗磷酸丝氨酸抗体和酶去磷酸化分离的DRPLA蛋白复合体的免疫印迹研究使我们能够证明，作为第三种疾病过程，DRPLA蛋白复合体在DRPLA脑组织中异常磷酸化。较少

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