The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease
The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease
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DOI：
10.1093/brain/awh054
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发表时间：
2004-02-01
期刊：
影响因子：
14.5
通讯作者：
Lees, AJ
中科院分区：
文献类型：
--
作者：
Bandopadhyay, R;Kingsbury, AE;Lees, AJ
染色体1p36上的DJ-1基因的两个突变最近已被确定导致早发性常染色体隐性帕金森病。由于没有关于DJ-1蛋白在人脑中的分布的信息，在本研究中，我们使用DJ-1的单克隆抗体来绘制其在额叶皮层和黑质中的分布，这两个区域总是与帕金森病有关。人类额叶皮层的Western blotting结果显示，DJ-1在对照、特发性帕金森病、临床和病理表型为DJ-1 R98Q多态性的帕金森病患者以及进行性核上性麻痹（PSP）脑中都是一个丰富的蛋白。我们还发现，DJ-1免疫反应性（IR）在对照和帕金森病额叶皮层的星形胶质细胞和星形胶质细胞过程中都特别突出，而神经元则表现出轻微或没有DJ-1 IR。只有偶尔的路易体（LBs），帕金森病的病理标志，显示微弱的DJ-1 IR，局限于外晕。在临床前研究中，我们发现DJ-1在小鼠大脑的原代海马和星形胶质细胞中表达。通过二维凝胶分析，我们还发现，在对照组和帕金森病大脑中，DJ-1的多种pI异构体在5.5-6.6之间，而M17细胞暴露于氧化剂百草枯时，内源性DJ-1的pI向酸性更强的异构体转变。我们得出结论，DJ-1不是LBs和Lewy神经突的必需成分，主要由人脑组织中的星形胶质细胞表达，并且对氧化应激条件敏感。这些结果与神经元-神经胶质相互作用在帕金森病的病理生理学中很重要的假设是一致的。
Two mutations in the DJ-1 gene on chromosome1p36 have been identified recently to cause early-onset, autosomal recessive Parkinson's disease. As no information is available regarding the distribution of DJ-1 protein in the human brain, in this study we used a monoclonal antibody for DJ-1 to map its distribution in frontal cortex and substantia nigra, regions invariably involved in Parkinson's disease. Western blotting of human frontal cortex showed DJ-1 to be an abundant protein in control, idiopathic Parkinson's disease, cases with clinical and pathological phenotypes of Parkinson's disease with R98Q polymorphism for DJ-1, and in progressive supranuclear palsy (PSP) brains. We also showed that DJ-1 immunoreactivity (IR) was particularly prominent in astrocytes and astrocytic processes in both control and Parkinson's disease frontal cortex, whereas neurons showed light or no DJ-1 IR. Only occasional Lewy bodies (LBs), the pathological hallmarks of Parkinson's disease, showed faint DJ-1 IR, localized to the outer halo. In preclinical studies we showed that DJ-1 is expressed in primary hippocampal and astrocyte cultures of mouse brain. By 2D gel analysis we also showed multiple pI isoforms for DJ-1 ranging between 5.5-6.6 in both control and Parkinson's disease brains, whilst exposure of M17 cells to the oxidizing agent paraquat was manifested as a shift in pI of endogenous DJ-1 towards more acidic isoforms. We conclude that DJ-1 is not an essential component of LBs and Lewy neurites, is expressed mainly by astrocytes in human brain tissue and is sensitive to oxidative stress conditions. These results are consistent with the hypothesis that neuronal-glial interactions are important in the pathophysiology of Parkinson's disease.