the role of molecular chaperones in α-synuclein-related diseases

分子伴侣在α-突触核蛋白相关疾病中的作用

基本信息

批准号：
15590887
负责人：
KAWAMOTO Yasuhiro
金额：
$ 2.24万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

14-3-3 proteins, a novel type of molecular chaperons, recognizes the phosphoserine-containing motifs of several target proteins, and regulates various types of signal transduction pathways. We have already reported that 14-3-3 immunoreactivity was localized to the α-synuclein-containing inclusins in brains with Parkinso's disease and multiple system atrophy. We then examined the brains and spinal cords of human α-synuclein (A53T) transgenic mice, and found the immunohistochemical colocalization of α-synuclein and 14-3-3 proteins. We also observed the increased immunoreactivities for some heat shock proteins in brains with synucleinopathies. Furthermore, we performed immunohistochemical studies on 14-3-3 proteins using autopsied spinal cord from patients with amyotrophic lateral sclerosis (ALS), and found 14-3-3 immunoreactivity in the Lewy body-like hyaline inclusions from both sporadic and familial ALS cases. We also observed that 14-3-3 immunoreactivity was localized to the α-synuclein-containing inclusinsin in the anterior horn cells from human SOD1(G93T) trausgenic mice. Moreover, we found the enhanced astroglial immunoexpression of 14-3-3 in the demyelinated lesions from patients with multiple sclerosis and progressive multifocal leukoencephalopathy, and in the cortical and subcortical lesions from patients with Creutzfeldt-Jakob disease, and in the ischemic white matter lesions from Binswanger's disease cases. These data suggest that 14-3-3 proteins may play an important role in the formation of several types of inclusions in brains with neurodegenerative diseases, and that 14-3-3 proteins may be induced in astrocytes under various kinds of pathological conditions, including demyelination, inflammation, and ischemia, and may be associated with the formation of astrogliosis.

14-3-3蛋白是一种新型的分子链蛋白，识别几种靶蛋白的含磷酸氨基蛋白基序，并调节各种类型的信号转导途径。我们已经报道说，14-3-3的免疫反应性定位于患有帕克尼氏病和多个系统萎缩的大脑中含有α-核蛋白的含素。然后，我们检查了人α-突触核蛋白（A53T）转基因小鼠的大脑和脊髓，并发现了α-突触核蛋白和14-3-3蛋白的免疫组织化学共定位。我们还观察到了与突触核苷病的大脑中某些热休克蛋白的免疫反应性增加。此外，我们使用肌萎缩性外侧硬化症患者（ALS）患者的脊髓对14-3-3蛋白进行了免疫组织化学研究，并发现了来自孢子虫和家庭ALS病例的Lewy身体样透明透明质酸的14-3-3免疫反应性。我们还观察到，在人类SOD1（G93T）创伤性小鼠的前角细胞中，将14-3-3的免疫反应性定位于含α-突触蛋白的含素蛋白。此外，我们发现，来自多发性硬化症和进行性多焦点白细胞造成性的脱髓鞘病变中的星形胶质体免疫表达增强，以及皮质和皮质下病变中的皮质和皮层损伤，来自患有Creutzfeldt-Jakob疾病的患者，以及在同性疾病中的Creutzfeldt-Jakob疾病。这些数据表明，14-3-3蛋白可能在神经退行性疾病的大脑中形成几种类型的夹杂物中起重要作用，并且在各种病理状况下，在星形胶质细胞中可能会诱导14-3-3蛋白，包括各种病理疾病，包括脱叶，炎症，炎症和性部脉冲和性部质量和质量性和天文学作用。