2004-10-11 16:00:00

帕金森症的一个胚胎干细胞模型

未知

帕金森症（Parkinson’s disease）的主要症状包括：颤抖、僵硬、行动迟缓、行走困难等。当大约50%的多巴胺（dopamine）神经元退化死亡之后，帕金森症的症状就会开始出现，但目前这种神经元退化的分子机制还不清楚。事实上，解开多巴胺神经元退化之谜的一个难点就是找到一种能够精确模拟多巴胺细胞损失的模型。

        在PLoS Biology上的发表的两篇文章叙述了，Asa Abeliovich和同事用小鼠胚胎干细胞构建这种疾病模型的过程，从而为帕金森症的疾病机制研究奠定了基础。

        研究人员利用小鼠胚胎干细胞创造出缺乏DJ-1（在一种遗传型的帕金森症中发生突变的一种基因）的多巴胺神经元。他们在第一篇文章中报道说缺乏DJ-1基因的细胞，尤其是缺乏DJ-1的多巴胺神经元对氧化压力的敏感性增加。这种氧化压力由氧代谢产生。在第二篇文章中，研究人员将DJ-1的功能障碍与alpha-synuclein的积累联系在一起。已知alpha-synclein是帕金森症的一个标志物质。

        尽管人们早就知道神经退行性疾病和神经细胞死亡与氧化压力有关。但是，要想找到他们之间的因果关系就必须找到分子机制。这些新的研究结果证明了氧化损伤与疾病的关系并且为神经退行性疾病以及有潜力的治疗药物的筛选提供了一个可操作的模型。

相关图片

journal-pbio-0020327-g005

Figure 5. RNAi “Knockdown” of DJ-1 in Primary Embryonic Midbrain DNs Display Increased Sensitivity to Oxidative Stress

	(A–P) Primary midbrain cultures from E13.5 embryos were infected with lentiviral vectors encoding DJ-1 shRNA (or vector alone) under the regulation of the control vector (A–H) or the U6 promoter (I–P). Cells were cultured for 1 wk after infection and then exposed to H₂O₂ (5 μM; E–H and M–P) for 24 h. Cultures were immunostained for TH (B, F, J, and N) or DAT (C, G, K, or O) and visualized by confocal microscopy. Images containing all stains are included (Merge; D, H, L, and P). Scale bar, 100 μm.
	(Q) Cell lysates prepared from midbrain primary cultures infected with DJ-1 shRNA lentivirus (or control vector) were analyzed by Western blotting for murine DJ-1 or β-actin.
	(R–T) Quantification of TH, DAT, and GFP signal was performed on ten randomly selected fields in each of three wells for each condition. Red triangles, DJ-1 shRNA treated; black circles, control vector. Data represent the means ± SEM and were analyzed by ANOVA followed by Fisher's post-hoc test. * p 0.05.