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Molecular pathomechanisms in alpha-synucleinopathis

α-突触核蛋白病的分子病理机制

基本信息

批准号：
14570576
负责人：
WAKABAYASHI Koichi
金额：
$ 2.11万
依托单位：
Hirosaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

In 2002, we carried out immunohistochemical examinations of the cerebella of patients with Parkinson's disease (PD), diffuse Lewy body disease (DLBD) or multiple system atrophy (MSA), using antibodies specific for alpha-synuclein (aS). aS-positive doughnut-shaped structures were found occasionally in the cerebellar molecular layer in some of these patients. Double-labeling immunofluorescence and immunoelectron microscopy studies revealed that these aS-positive doughnut-shaped structures were located in the GFAP-positive radial processes of Bergmann glia, corresponding to the outer area of Lewy body (LB)-like inclusions, and consisted of granulo-filamentous structures. These findings indicate that, although not frequently, Bergmann glia of the cerebellum are also the targets of aS pathology in alpha-synucleinopathies.In 2003, we immunohistochemically examined the MSA brain, using specific antibodies against aS and beta-synuclein(bS). aS-positive filamentous aggregates were frequently fo … More und in neurons in the pontine and inferior olivary nuclei. No abnormal accumulation of aS was noted in Purkinje cells. In contrast, bS accumulation occurred extensively in Purkinje cells, and only minimally in pontine and olivary neurons. Thus, neuronal aS inclusions appear to occur only rarely in neurons in which bS accumulates. These findings support the possibility that bS is a negative regulator of aS aggregation.In 2004, we performed immunohistochemical staining of brain tissue from patients with various neurodegenerative disorders, using an affinity-purified polyclonal antibody raised against NEDD8 that did not cross-react with ubiquitin. In LB disease, NEDD8 immunoreactivity was present in almost all of the LBs and Lewy neurites. Moreover, NEDD8 immunoreactivity was found in a variety of ubiquitinated inclusions, including neuronal and oligodendroglial inclusions in multiple system atrophy, neurofibrillary tangles in Alzheimer's disease, ubiquitinated inclusions in motor neurone disease, and intranuclear inclusions in triplet repeat diseases. These findings suggest that NEDD8 is involved in the formation of various ubiquitinated inclusions via the ubiquitin-proteasome system. Less

在2002年，我们进行了免疫组织化学检查的患者与帕金森氏病（PD），弥漫性路易体病（DLBD）或多系统萎缩症（MSA），使用特异性抗体的α-突触核蛋白（aS）的小脑。在部分患者的小脑分子层中偶见aS阳性的甜甜圈状结构。免疫荧光和免疫电镜双标记研究表明，这些aS阳性的环状结构位于Bergmann胶质细胞GFAP阳性的放射状突起内，相当于Lewy小体（LB）样包涵体的外侧区域，由颗粒-丝状结构组成。这些研究结果表明，虽然不经常，小脑的伯格曼神经胶质细胞也是目标的aS病理在α-synucleinopathies.In 2003年，我们化学方法检查了MSA的大脑，使用特异性抗体对aS和β-synuclein（bS）。aS阳性的丝状聚集体经常出现， ...更多信息以及脑桥和下橄榄核的神经元。在浦肯野细胞中未观察到aS的异常蓄积。相反，bS积累广泛发生在浦肯野细胞，只有最低限度的脑桥和橄榄神经元。因此，神经元的aS夹杂物似乎很少发生在神经元中的bS积累。这些研究结果支持的可能性，bS是一个负调节器的aS aggregation.In 2004年，我们进行了免疫组化染色的脑组织从患者的各种神经退行性疾病，使用亲和纯化的多克隆抗体提出了对NEDD 8，不与泛素交叉反应。在LB疾病中，NEDD 8免疫反应性存在于几乎所有的LB和路易神经突中。此外，NEDD 8免疫反应性被发现在各种泛素化的包涵体，包括神经元和少突胶质细胞包涵体在多系统萎缩，神经元缠结在阿尔茨海默氏病，泛素化包涵体运动神经元疾病，和核内包涵体在三联重复疾病。这些发现表明，NEDD 8通过泛素-蛋白酶体系统参与各种泛素化包涵体的形成。少