帕金森癥（Parkinson’s disease）的主要癥狀包括：顫抖、僵硬,、行動(dòng)遲緩,、行走困難等。當(dāng)大約50%的多巴胺（dopamine）神經(jīng)元退化死亡之后,，帕金森癥的癥狀就會(huì)開始出現(xiàn),，但目前這種神經(jīng)元退化的分子機(jī)制還不清楚。事實(shí)上,，解開多巴胺神經(jīng)元退化之謎的一個(gè)難點(diǎn)就是找到一種能夠精確模擬多巴胺細(xì)胞損失的模型,。
在PLoS Biology上的發(fā)表的兩篇文章敘述了，Asa Abeliovich和同事用小鼠胚胎干細(xì)胞構(gòu)建這種疾病模型的過程，從而為帕金森癥的疾病機(jī)制研究奠定了基礎(chǔ),。
研究人員利用小鼠胚胎干細(xì)胞創(chuàng)造出缺乏DJ-1（在一種遺傳型的帕金森癥中發(fā)生突變的一種基因）的多巴胺神經(jīng)元,。他們?cè)诘谝黄恼轮袌?bào)道說缺乏DJ-1基因的細(xì)胞，尤其是缺乏DJ-1的多巴胺神經(jīng)元對(duì)氧化壓力的敏感性增加,。這種氧化壓力由氧代謝產(chǎn)生,。在第二篇文章中，研究人員將DJ-1的功能障礙與alpha-synuclein的積累聯(lián)系在一起,。已知alpha-synclein是帕金森癥的一個(gè)標(biāo)志物質(zhì),。
盡管人們?cè)缇椭郎窠?jīng)退行性疾病和神經(jīng)細(xì)胞死亡與氧化壓力有關(guān)。但是,，要想找到他們之間的因果關(guān)系就必須找到分子機(jī)制。這些新的研究結(jié)果證明了氧化損傷與疾病的關(guān)系并且為神經(jīng)退行性疾病以及有潛力的治療藥物的篩選提供了一個(gè)可操作的模型,。
相關(guān)圖片
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.
全文
http://www.plosbiology.org/plosonline/?request=get-document&doi=10.1371/journal.pbio.0020362
http://www.plosbiology.org/plosonline/?request=get-document&doi=10.1371/journal.pbio.0020327
