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

齿状核-苍白球路易体萎缩（DRPLA）蛋白在DRPLA脑组织中的病理作用

基本信息

批准号：
11670652
负责人：
YAZAWA Ikuru
金额：
$ 1.41万
依托单位：
Okinaka Memorial Institute for Medical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

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

近十到二十年来，日本患有 2 型糖尿病的患者数量急剧增加，至少部分原因是饮食习惯和久坐生活方式的西化。此前，人们认为与日本人胰岛素分泌受损发病机制相关的基因比与胰岛素抵抗发展相关的基因更重要。然而，最近的观察表明，那些导致胰岛素抵抗或肥胖发生的基因同样重要。我们从无关的日本 2 型糖尿病患者中提取了基因组 DNA。我们研究了多态性的关联，据报道，多态性存在于 2 型糖尿病发展的候选基因附近。我们还调查了我们发现的这些基因变异与日本 2 型糖尿病之间可能存在的关联。我们未能发现遗传变异与 2 型糖尿病之间存在显着关联。增加 DNA 样本数量似乎对于识别糖尿病发生的易感基因是必要的。谷氨酰胺重复（聚谷氨酰胺）疾病是一组遗传性神经退行性疾病，由相关基因产物中谷氨酰胺重复的扩展引起。该组包括亨廷顿病 (HD) 和齿状红核-苍白球路易斯萎缩症 (DRPLA)。在 HD 和 DRPLA 患者的脑组织中发现了与该基因产物表现出免疫反应性的神经元核内和细胞质内含物。携带扩展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 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 患者脑组织中发生了涉及 DRPLA 基因产物（DRPLA 蛋白）的异常蛋白质复合物形成而引起的多种疾病过程。第一个过程是由于 DRPLA 蛋白分子之间异常牢固的结合而形成大型复合物。第二个是 DRPLA 蛋白复合物的病理性泛素化。使用抗磷酸丝氨酸抗体和酶促去磷酸化分离的 DRPLA 蛋白复合物的免疫印迹研究最近使我们能够证明 DRPLA 蛋白复合物在 DRPLA 脑组织中异常磷酸化，这是第三种疾病过程。较少的