Nurr1 in Parkinson's disease and related disorders
Nurr1 in Parkinson's disease and related disorders
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DOI：
10.1002/cne.20828
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发表时间：
2006-01-20
影响因子：
2.5
通讯作者：
Kordower, JH
中科院分区：
文献类型：
--
作者：
Chu, YP;Le, WD;Kordower, JH
在哺乳动物中，转录因子Nurr 1在发育早期表达，并在整个生物体的一生中持续可检测。Nurr 1参与特定中枢神经系统神经元亚群（包括黑质纹状体多巴胺系统）内多巴胺能表型的建立和维持。这种蛋白质在正常衰老过程中减少，这是帕金森病（PD）的主要危险因素。然而，Nurr 1表达是否受PD的影响还没有记录。本研究检测了Nurr 1在PD患者黑质神经元内多巴胺能表型维持中的作用，并与诊断为进行性核上性麻痹（PSP）或阿尔茨海默病（AD）的患者或年龄匹配的对照组进行比较。在PD中，含有α-突触核蛋白免疫反应性包涵体的黑质神经元中Nurr 1免疫荧光的光密度（OD）显著降低。类似地，AD病例黑质中Nurr 1免疫荧光强度的OD在具有神经元缠结（NFT）的神经元中降低。与PD和AD相比，PSP病例中Nurr 1免疫荧光强度的OD值在有或没有NFT的神经元中均严重降低。Nurr 1-ir神经元数量和OD值在PD的黑质（SN）神经元内观察到下降，但在海马神经元内没有观察到。Nurr 1-ir表达的下降与四组中酪氨酸羟化酶免疫荧光的丧失相关。这些数据表明，多巴胺能神经元中的Nurr 1缺陷与突触核蛋白病和tau蛋白病中的细胞内病理学相关。
In mammals, the transcription factor Nurr1 is expressed early in development and continues to be detectable throughout the organism's lifetime. Nurr1 is involved in the establishment and maintenance of the dopaminergic phenotype within specific central nervous system neuronal subpopulations including the nigrostriatal dopamine system. This protein is reduced over the course of normal aging, which is a major risk factor for Parkinson's disease (PD). However, whether Nurr1 expression is affected by PD has not been documented. The present study examined the role of Nurr1 in the maintenance of the dopaminergic phenotype within neurons in substantia nigra in PD compared with patients with diagnoses of progressive supranuclear palsy (PSP) or Alzheimer's disease (AD) or age-matched-matched controls. In PD, the optical density (OD) of Nurr1 immunofluorescence was significantly decreased in nigral neurons containing alpha-synuclein-immunoreactive inclusions. Similarly, the OD of Nurr1 immunofluorescence intensity in the nigra of AD cases was decreased in neurons with neurofibrillary tangles (NFTs). In contrast to PD and AD, the OD of Nurr1 immunofluorescence intensity was severely decreased in the neurons with or without NFTs in PSP cases. Decline of Nurr1-ir neuronal number and OD was observed within substantia nigra (SN) neurons in PD but not within hippocampal neurons. The decline in Nurr1-ir expression was correlated with loss of tyrosine hydroxylase immunofluorescence across the four groups. These data demonstrate that Nurr1 deficiency in dopaminergic neurons is associated with the intracellular pathology in both synucleinopathies and tauopathies.