Molecular pathomechanisms in alpha-synucleinopathis

2002年，我们使用α -突触核蛋白（aS）特异性抗体对帕金森病（PD）、弥漫性路易体病（DLBD）或多系统萎缩（MSA）患者的小脑进行了免疫组化检查。在这些患者中，偶尔在小脑分子层发现as阳性的甜甜圈状结构。双标记免疫荧光和免疫电镜研究显示，这些as阳性的甜甜圈状结构位于Bergmann胶质细胞gfap阳性的径向突起，与路易体（LB）样包涵体的外侧区域相对应，由颗粒-丝状结构组成。这些发现表明，尽管不常见，小脑的伯格曼胶质细胞也是α -突触核蛋白病aS病理的目标。2003年，我们使用针对aS和β -突触核蛋白（bS）的特异性抗体对MSA脑进行了免疫组织化学检查。as阳性丝状聚集体多见于脑桥核和下橄榄核的神经元。浦肯野细胞未见aS异常积聚。相比之下，bS的积累在浦肯野细胞中广泛发生，而在脑桥和橄榄神经元中则很少发生。因此，神经元aS包涵体似乎很少出现在bS积聚的神经元中。这些发现支持bS是aS聚集的负调节因子的可能性。2004年，我们对各种神经退行性疾病患者的脑组织进行了免疫组织化学染色，使用了一种针对NEDD8的亲和纯化多克隆抗体，该抗体不与泛素交叉反应。在LB疾病中，NEDD8免疫反应性几乎存在于所有的LB和Lewy神经突中。此外，在多种泛素化包涵体中发现了NEDD8的免疫反应性，包括多系统萎缩的神经元和少突胶质包涵体、阿尔茨海默病的神经原纤维缠结、运动神经元疾病的泛素化包涵体和三重重复疾病的核内包涵体。这些发现表明NEDD8通过泛素-蛋白酶体系统参与了各种泛素化包体的形成。少

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