Pattarini R, Smeyne R J, Morgan J I
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Danny Thomas Research Tower, Room D2025E, Mail Stop 323, Memphis, TN 38105-2794, USA.
Neuroscience. 2007 Mar 16;145(2):654-68. doi: 10.1016/j.neuroscience.2006.12.030. Epub 2007 Jan 29.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). With the exception of a few rare familial forms of the disease, the precise molecular mechanisms underlying PD are unknown. Inflammation is a common finding in the PD brain, but due to the limitation of postmortem analysis its relationship to disease progression cannot be established. However, studies using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have also identified inflammatory responses in the nigrostriatal pathway that precede neuronal degeneration in the SNpc. To assess the pathological relevance of these inflammatory responses and to identify candidate genes that might contribute to neuronal vulnerability, we used quantitative reverse-transcription polymerase chain reaction (qRT-PCR) to measure mRNA levels of 11 cytokine and chemokine encoding genes in the striatum of MPTP-sensitive (C57BL/6J) and MPTP-insensitive (Swiss Webster, SWR) mice following administration of MPTP. The mRNA levels of all 11 genes changed following MPTP treatment, indicating the presence of inflammatory responses in both strains. Furthermore, of the 11 genes examined only 3, interleukin 6 (Il-6), macrophage inflammatory protein 1 alpha/CC chemokine ligand 3 (Mip-1alpha/Ccl3) and macrophage inflammatory protein 1 beta/CC chemokine ligand 4 (Mip-1beta/Ccl4), were differentially regulated between C57BL/6J and SWR mice. In both mouse strains, the level of monocyte chemoattractant protein 1/CC chemokine ligand 2 (Mcp-1/Ccl2) mRNA was the first to increase following MPTP administration, and might represent a key initiating component of the inflammatory response. Using Mcp-1/Ccl2 knockout mice backcrossed onto a C57BL/6J background we found that MPTP-stimulated Mip-1alpha/Ccl3 and Mip-1beta/Ccl4 mRNA expression was significantly lower in the knockout mice; suggesting that Mcp-1/Ccl2 contributes to MPTP-enhanced expression of Mip-1alpha/Ccl3 and Mip-1beta/Ccl4. However, stereological analysis of SNpc neuronal loss in Mcp-1/Ccl2 knockout and wild-type mice showed no differences. These findings suggest that it is the ability of dopaminergic SNpc neurons to survive an inflammatory insult, rather than genetically determined differences in the inflammatory response itself, that underlie the molecular basis of MPTP resistance.
帕金森病(PD)是一种神经退行性疾病,其特征是黑质致密部(SNpc)中的多巴胺能神经元丧失。除了少数罕见的家族性形式的疾病外,PD潜在的确切分子机制尚不清楚。炎症是PD大脑中的常见现象,但由于死后分析的局限性,其与疾病进展的关系无法确定。然而,使用1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的PD模型的研究也发现,黑质纹状体通路中的炎症反应先于SNpc中的神经元变性。为了评估这些炎症反应的病理相关性并确定可能导致神经元易损性的候选基因,我们使用定量逆转录聚合酶链反应(qRT-PCR)来测量MPTP敏感型(C57BL/6J)和MPTP不敏感型(瑞士韦伯斯特,SWR)小鼠纹状体中11种细胞因子和趋化因子编码基因的mRNA水平。在给予MPTP后,所有11个基因的mRNA水平均发生变化,表明两种品系中均存在炎症反应。此外,在检测的11个基因中,只有3个基因,即白细胞介素6(Il-6)、巨噬细胞炎性蛋白1α/CC趋化因子配体3(Mip-1α/Ccl3)和巨噬细胞炎性蛋白1β/CC趋化因子配体4(Mip-1β/Ccl4),在C57BL/6J和SWR小鼠之间存在差异调节。在两种小鼠品系中,单核细胞趋化蛋白1/CC趋化因子配体2(Mcp-1/Ccl2)mRNA水平在给予MPTP后最先升高,可能代表炎症反应的关键起始成分。使用回交到C57BL/6J背景的Mcp-1/Ccl2基因敲除小鼠,我们发现敲除小鼠中MPTP刺激的Mip-1α/Ccl3和Mip-1β/Ccl4 mRNA表达显著降低;这表明Mcp-1/Ccl2有助于MPTP增强Mip-1α/Ccl3和Mip-1β/Ccl4的表达。然而,对Mcp-1/Ccl2基因敲除小鼠和野生型小鼠SNpc神经元损失的体视学分析显示没有差异。这些发现表明,多巴胺能SNpc神经元在炎症损伤中存活的能力,而非炎症反应本身的基因决定差异,是MPTP抗性分子基础的原因。