Role of NUB1 in inclusion body formation in neurodegenerative disorders

最近，我们发现NUB1是一种突触蛋白-1相互作用蛋白，并且NUB1和突触蛋白-1在帕金森病（PD）和路易体痴呆（DLB）的路易体中积累，在多系统萎缩（MSA）的胶质细胞质内含物中积累。本研究进一步研究了NUB1在各种神经退行性疾病中的免疫组织化学定位。在对照组中，抗nub1抗体弱免疫标记神经元核周。在PD和DLB中，皮层型和脑干型路易小体、苍白小体和路易神经突被抗nub1强烈免疫标记。在MSA中，在神经元和少突胶质细胞的胞浆内包涵体、神经元核包涵体和肿胀的神经突中都发现了NUB1免疫反应性。在其他疾病的多种其他神经元或胶质包涵体中未发现NUB1免疫反应性，包括阿尔茨海默病、皮克病、进行性核上性麻痹、皮质基底变性…More ation、运动神经元疾病和三重重复疾病。这些发现提示NUB的异常积累！对α-突触核蛋白病变有特异性。接下来，我们使用抗磷酸化α-突触核蛋白（αS）抗体对25例具有不同程度路易体病理的症状性和症状前PD患者的新纹状体进行免疫组织化学检测。根据Braak等人提出的PD分期对这些患者进行分类。αS免疫组化显示新纹状体中有神经元和胶质细胞质包涵体和神经性质的改变。αS包涵体存在于中等神经元（投射到苍白球的gaba能神经元）和大神经元（胆碱能中间神经元）；前者在III期开始出现，后者在V、VI期出现。III期也开始出现神经性改变和胶质包涵体。神经元和胶质包涵体的数量以及神经性病变的程度与PD分期相关（p<0.001）。这些结果表明，PD进展过程中，内生性新纹状体神经元通过αS聚集变性。少

Recently, we showed that NUB1 is a synphilin-1-interacting protein and that NUB1, as well as synphilin-1, accumulates in Lewy bodies in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and glial cytoplasmic inclusions in multiple system atrophy (MSA). In this study, an investigation was further conducted to elucidate the immunohistochemical localization of NUB1 in various neurodegenerative disorders. In controls, anti-NUB1 antibody weakly immunolabeled the neuronal perikarya. In PD and DLB, cortical and brainstem-type Lewy bodies, pale bodies and Lewy neurites were strongly immunolabeled with anti-NUB1. In MSA, NUB1 immunoreactivity was found in the intracytoplasmic inclusions of both neuronal and oligodendroglial cells, neuronal nuclear inclusions, and swollen neurites. No NUB1 immunoreactivity was found in a variety of other neuronal or glial inclusions in other disorders, including Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degener … More ation, motor neuron disease and triplet-repeat diseases. These findings indicate that the abnormal accumulation of NUB! is specific for α-synucleinopathy lesions.Next, we immunohistochemically examined the neostriatum from 25 patients with symptomatic and presymptomatic PD with various degrees of Lewy body pathology, using anti-phosphorylated α-synuclein (αS) antibody. These patients were classified, according to the PD staging proposed by Braak et al. αS immunohistochemistry revealed neuronal and glial cytoplasmic inclusions and neuritic changes in the neostriatum. αS inclusions were found in the medium-sized neurons (GABAergic neurons that project to the globus pallidus) and large neurons (cholinergic interneurons); the former began to appear at stage III and the latter was noted at stages V and VI. Neuritic changes and glial inclusions also began to appear at stage III. The numbers of neuronal and glial inclusions and the extent of neuritic changes correlated with the PD stage (p<0.001). These findings-suggest that intrinsic neostriatal neurons degenerate through αS aggregation during PD progression. Less