CXCR4 and CXCL12 Expression is Increased in the Nigro-Striatal System of Parkinson's Disease
CXCR4 and CXCL12 Expression is Increased in the Nigro-Striatal System of Parkinson's Disease
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DOI：
10.1007/s12640-009-9076-3
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发表时间：
2009-10-01
影响因子：
3.7
通讯作者：
Mocchetti, Italo
中科院分区：
文献类型：
--
作者：
Shimoji, Mika;Pagan, Fernando;Mocchetti, Italo
除了少数与已知基因缺陷相关的遗传病例外，帕金森病（PD）是一种病因不明的散发性神经退行性疾病。越来越多的证据表明，小胶质细胞的炎症和增殖可能导致PD患者黑质纹状体多巴胺能系统的神经元损伤。参与神经元损伤的小胶质细胞事件包括促炎因子和神经毒性因子的释放。表征这些因素可能有助于预防PD症状的恶化或纠正疾病进展。在啮齿类动物中，黑质纹状体系统显示出趋化因子受体CXCR4的高表达。其天然配体CXCL12可促进神经元凋亡。因此，本研究研究了CXCR4和CXCL12在PD和对照（非PD）个体死后大脑以及PD动物模型中的表达。在人黑质（SN）中，CXCR4免疫反应性在多巴胺能神经元中较高。有趣的是，尽管多巴胺（DA）神经元缺失，PD组SN中CXCR4和CXCL12的表达高于对照组。这种效果伴随着激活的小胶质细胞的增加。然而，死后脑的结果可能无法提供CXCL12/CXCR4是否会导致DA神经元变性的指示。为了检验这些趋化因子的作用，我们测定了mptp处理小鼠SN中CXCL12和CXCR4的水平。MPTP在DA神经元丢失之前产生了时间依赖性的CXCR4上调。这些结果提示CXCL12/CXCR4可能参与PD的发病过程，并提示PD可能的新靶点分子。
Except for a handful of inherited cases related to known gene defects, Parkinson's disease (PD) is a sporadic neurodegenerative disease of unknown etiology. There is increasing evidence that inflammation and proliferation of microglia may contribute to the neuronal damage seen in the nigro-striatal dopaminergic system of PD patients. Microglia events that participate in neuronal injury include the release of pro-inflammatory and neurotoxic factors. Characterizing these factors may help to prevent the exacerbation of PD symptoms or to remediate the disease progression. In rodents, the nigro-striatal system exhibits high expression of the chemokine receptor CXCR4. Its natural ligand CXCL12 can promote neuronal apoptosis. Therefore, the present study investigated the expression of CXCR4 and CXCL12 in post-mortem brains of PD and control (non-PD) individuals and in an animal model of PD. In the human substantia nigra (SN), CXCR4 immunoreactivity was high in dopaminergic neurons. Interestingly, the SN of PD subjects exhibited higher expression of CXCR4 expression and CXCL12 than control subjects despite the loss of dopamine (DA) neurons. This effect was accompanied by an increase in activated microglia. However, results from post-mortem brains may not provide indication as to whether CXCL12/CXCR4 can cause the degeneration of DA neurons. To examine the role of these chemokines, we determined the levels of CXCL12 and CXCR4 in the SN of MPTP-treated mice. MPTP produced a time-dependent up-regulation of CXCR4 that preceded the loss of DA neurons. These results suggest that CXCL12/CXCR4 may participate in the etiology of PD and indicate a new possible target molecule for PD.