Jokic Natasa, Ling Yong Yong, Ward Rachael E, Michael-Titus Adina T, Priestley John V, Malaspina Andrea
Neuroscience Centre, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
J Neurochem. 2007 Dec;103(5):1821-33. doi: 10.1111/j.1471-4159.2007.04893.x. Epub 2007 Sep 13.
Changes in distribution and expression of retinoid receptors may be part of a spinal cord protective response to acute injury and to chronic degeneration. In this study, we have combined RNA and protein expression analysis to characterize the expression profile of retinoid receptors in the lumbar spinal cord of the superoxide dismutase 1 G93A mutant rat model of amyotrophic lateral sclerosis, a fatal neurodegenerative disorder causing extensive motor neuron loss. We also report a nonsignificant change in RNA expression of binding proteins and metabolizing enzymes for retinol and retinoic acid in the mutant rat spinal cord at end-stage disease. Only retinoid X receptor beta (RXRbeta), and to a lesser extent retinoic acid receptor beta and alpha (RARbeta/alpha) were reliably detected in lumbar spinal cord at an early pre-symptomatic phase and throughout the disease progression. The expression of RXRbeta in lamina II neurons in the dorsal horn of transgenic and wild type (WT) animals was associated with extensive astrocyte staining in end-stage lumbar spinal cord from transgenic rats. RARbeta and RARalpha diffuse staining of large motor neurons in the pre-symptomatic transgenic and in the WT lumbar cord appear to decline in end-stage disease, when a selective and strong gamma motor neuron RARalpha staining becomes evident. As gliosis and motor neuron loss are key pathogenic features in amyotrophic lateral sclerosis, the selective expression of retinoid receptors in astrocytes and motor neurons may provide further clues to the role of retinoid signalling in neurodegeneration and suggest new treatment strategies based on retinoid-modulating agents.
维甲酸受体分布和表达的变化可能是脊髓对急性损伤和慢性退变的一种保护反应的一部分。在本研究中，我们结合了RNA和蛋白质表达分析，以表征维甲酸受体在肌萎缩侧索硬化症超氧化物歧化酶1 G93A突变大鼠模型腰脊髓中的表达谱，肌萎缩侧索硬化症是一种致命的神经退行性疾病，会导致大量运动神经元丧失。我们还报告了在疾病终末期，突变大鼠脊髓中视黄醇和视黄酸结合蛋白及代谢酶的RNA表达无显著变化。仅在症状前期早期及整个疾病进展过程中，在腰脊髓中可靠地检测到了维甲酸X受体β（RXRβ），视黄酸受体β和α（RARβ/α）的检测程度较低。在转基因和野生型（WT）动物背角II层神经元中，RXRβ的表达与转基因大鼠终末期腰脊髓中广泛出现的星形胶质细胞染色有关。在症状前期转基因和WT腰脊髓中，大运动神经元的RARβ和RARα弥漫性染色在疾病终末期似乎下降，此时选择性且强烈的γ运动神经元RARα染色变得明显。由于胶质增生和运动神经元丧失是肌萎缩侧索硬化症的关键致病特征，维甲酸受体在星形胶质细胞和运动神经元中的选择性表达可能为维甲酸信号在神经退行性变中的作用提供进一步线索，并提示基于维甲酸调节剂的新治疗策略。
