Centre for Neuroscience and Trauma, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Blizard Institute, 4 Newark Street, London E1 2AT, UK.
Neuroscience. 2010 Aug 25;169(2):812-27. doi: 10.1016/j.neuroscience.2010.04.053. Epub 2010 May 12.
It has been reported that an early activation of glial fibrillary acid protein (GFAP) in astroglial cells occurs simultaneously in peripheral nerves and spinal cord from the G93A SOD1 mouse model of amyotrophic lateral sclerosis (ALS), an invariably fatal neurodegenerative disorder. In ALS, the contribute to the pathological process of different cell types varies according to the disease stage, with a florid immune response in spinal cord at end stage disease. In this study, we have mapped in different anatomical sites the process of disease-induced functional perturbation from a pre-symptomatic stage using a marker of cellular distress expressed in neurons and glial cells, the activating transcription factor 3 (ATF-3), and applied large-scale gene expression analysis to define the pattern or transcriptional changes occurring in spinal cord from the G93A SOD1 rat model of ALS in parallel with ATF-3 neuronal activation. From the disease onset onward, transgenic lumbar spinal cord displayed ATF-3 transcriptional regulation and motor cells immunostaining in association with the over-expression of genes promoting cell growth, the functional integrity of cell organelles and involved in the modulation of immune responses. While spinal cord from the pre-symptomatic rat showed no detectable ATF-3 transcriptional regulation, ATF-3 activation was appreciated in large size neurofilament-rich, small size non-peptidergic and parvalbumin-positive neurons within the dorsal root ganglia (DRG), and in ventral roots Schwann cells alongside macrophages infiltration. This pattern of peripheral ATF-3 activation remained detectable throughout the disease process. In the G93A SOD1 rat model of ALS, signs of roots and nerves subtle distress preceded overt clinical-pathological changes, involving both glial cells and neurons that function as receptors of peripheral sensory stimuli from the muscle. In addition, factors previously described to be linked to ATF-3 activation under various experimental conditions of stress, become switched on in spinal cord from the end-stage transgenic rat model of ALS.
据报道，在肌萎缩侧索硬化症（ALS）的 G93A SOD1 小鼠模型中，星形胶质细胞中的胶质纤维酸性蛋白（GFAP）的早期激活同时发生在周围神经和脊髓中，这是一种不可避免的致命神经退行性疾病。在 ALS 中，不同细胞类型对病理过程的贡献因疾病阶段而异，在疾病晚期脊髓中出现明显的免疫反应。在这项研究中，我们使用神经元和神经胶质细胞中表达的细胞应激标志物激活转录因子 3（ATF-3），在不同解剖部位绘制了从预症状阶段开始的疾病诱导功能紊乱过程图谱，并且应用大规模基因表达分析来定义在 G93A SOD1 大鼠 ALS 模型的脊髓中发生的转录变化模式，同时与 ATF-3 神经元激活平行进行。从疾病发病开始，转基因腰脊髓显示 ATF-3 转录调节和运动细胞免疫染色，与促进细胞生长、细胞器功能完整性和参与免疫反应调节的基因的过度表达有关。虽然来自预症状大鼠的脊髓未检测到可检测的 ATF-3 转录调节，但在背根神经节（DRG）中的大型富含神经丝、小型非肽能和副甲状腺蛋白阳性神经元以及沿着巨噬细胞浸润的腹根 Schwann 细胞中观察到 ATF-3 激活。这种外周 ATF-3 激活模式在整个疾病过程中仍然可检测到。在 G93A SOD1 大鼠 ALS 模型中，根和神经的细微困扰迹象先于明显的临床病理变化，涉及到作为来自肌肉的外周感觉刺激受体的神经胶质细胞和神经元。此外，在各种应激实验条件下与 ATF-3 激活相关的先前描述的因素，在 ALS 转基因大鼠模型的终末期脊髓中被激活。
