Early functional deficit and microglial disturbances in a mouse model of amyotrophic lateral sclerosis.
Early functional deficit and microglial disturbances in a mouse model of amyotrophic lateral sclerosis.
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DOI：
10.1371/journal.pone.0036000
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Perrin FE
中科院分区：
文献类型：
--
作者：
Gerber YN;Sabourin JC;Rabano M;Vivanco Md;Perrin FE
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种以选择性运动神经元变性为特征的神经退行性疾病。目前还没有明确的发病顺序，也没有任何治疗方法。然而，越来越多的证据支持参与，除了神经元，几个合作伙伴，如胶质细胞和肌肉。为了更好地表征再现人类ALS症状的动物模型中病理事件的时间过程，我们研究了hSOD1G93A小鼠的功能和细胞特征。我们通过动态步行模式和自发运动活动分析评估了hSOD1G93A小鼠的运动功能。我们检测到早期功能缺陷，重新定义症状发作在60天的年龄，即20天前比以前描述的。此外，这些方法的顺序组合允许监测运动活动直到疾病终末期。为了初步将早期功能缺陷与细胞改变相关联，我们使用流式细胞术和免疫组织化学方法来表征神经肌肉接头、星形胶质细胞和小胶质细胞。我们发现（1）神经肌肉接头数量的减少与运动障碍相关，（2）星形胶质细胞的数量在症状前和早期年龄没有改变，但在症状发作时脊柱内的再分配发生了变化，（3）小胶质细胞的变化先于疾病发作。在症状出现前的年龄，我们发现小胶质细胞数量减少，而在发病时，两个不同的小胶质细胞亚群出现。总之，精确的运动分析更新了hSOD1G93A小鼠中疾病的发作，并允许运动监测直到疾病的末期。早期功能缺陷与神经肌肉接头的改变相一致。重要的是，我们确定了疾病发作前以及早期症状阶段小胶质细胞的不同变化。这一发现不仅在疾病的自然史中带来了一系列新的细胞事件，而且还可能为寻找疾病的生物标志物和潜在的治疗靶点提供线索。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by selective motoneurons degeneration. There is today no clear-cut pathogenesis sequence nor any treatment. However growing evidences are in favor of the involvement, besides neurons, of several partners such as glia and muscles. To better characterize the time course of pathological events in an animal model that recapitulates human ALS symptoms, we investigated functional and cellular characteristics of hSOD1G93A mice. We have evaluated locomotor function of hSOD1G93A mice through dynamic walking patterns and spontaneous motor activity analysis. We detected early functional deficits that redefine symptoms onset at 60 days of age, i.e. 20 days earlier than previously described. Moreover, sequential combination of these approaches allows monitoring of motor activity up to disease end stage. To tentatively correlate early functional deficit with cellular alterations we have used flow cytometry and immunohistochemistry approaches to characterize neuromuscular junctions, astrocytes and microglia. We show that (1) decrease in neuromuscular junction's number correlates with motor impairment, (2) astrocytes number is not altered at pre- and early-symptomatic ages but intraspinal repartition is modified at symptoms onset, and (3) microglia modifications precede disease onset. At pre-symptomatic age, we show a decrease in microglia number whereas at onset of the disease two distinct microglia sub-populations emerge. In conclusion, precise motor analysis updates the onset of the disease in hSOD1G93A mice and allows locomotor monitoring until the end stage of the disease. Early functional deficits coincide with alterations of neuromuscular junctions. Importantly, we identify different sets of changes in microglia before disease onset as well as at early-symptomatic stage. This finding not only brings a new sequence of cellular events in the natural history of the disease, but it may also provide clues in the search for biomarkers of the disease, and potential therapeutic targets.
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影响因子：
3.7
作者：
Mead RJ;Bennett EJ;Kennerley AJ;Sharp P;Sunyach C;Kasher P;Berwick J;Pettmann B;Battaglia G;Azzouz M;Grierson A;Shaw PJ
通讯作者：
Shaw PJ
影响因子：
3.7
作者：
Finkelstein A;Kunis G;Seksenyan A;Ronen A;Berkutzki T;Azoulay D;Koronyo-Hamaoui M;Schwartz M
通讯作者：
Schwartz M
影响因子：
9.9
作者：
Alexianu, ME;Kozovska, M;Appel, SH
通讯作者：
Appel, SH
影响因子：
8.3
作者：
Ito, D;Tanaka, K;Fukuuchi, Y
通讯作者：
Fukuuchi, Y
影响因子：
2.9
作者：
Mancuso, Renzo;Olivan, Sara;Navarro, Xavier
通讯作者：
Navarro, Xavier