Norris P J, Waldvogel H J, Faull R L, Love D R, Emson P C
Department of Neurobiology, Babraham Institute, Cambridge, U.K.
Neuroscience. 1996 Jun;72(4):1037-47. doi: 10.1016/0306-4522(95)00596-x.
The cellular abundance of neuronal nitric oxide synthase and somatostatin messenger RNAs was compared in the caudate nucleus, putamen and sensorimotor cortex of Huntington's disease and control cases. Neuronal nitric oxide synthase messenger RNA was significantly decreased in the caudate nucleus and putamen, but not in the sensorimotor cortex in Huntington's disease; the decrease in neuronal nitric oxide synthase messenger RNA became more pronounced with the severity of the disease. Somatostatin gene expression was significantly decreased in the dorsal putamen in Huntington's disease, but was essentially unchanged in all other regions examined. The density of neurons expressing detectable levels of neuronal nitric oxide synthase messenger RNA was reduced in the striata of Huntington's disease cases with advanced pathology; the density of neurons expressing detectable levels of somatostatin messenger RNA was similar in control and Huntington's disease cases. Neuropeptide Y-, somatostatin- and NADPH-diaphorase-positive neurons were consistently present throughout the striatum across all the grades of the disease. Neuronal nitric oxide synthase and NADPH-diaphorase activity (a histochemical marker for nitric oxide synthase-containing neurons) co-localize with somatostatin and neuropeptide Y in interneurons in the human striatum and cerebral cortex. Although the neurodegeneration associated with Huntington's disease is most evident in the striatum (particularly the dorsal regions), neuronal nitric oxide synthase/neuropeptide Y/somatostatin interneurons are relatively spared. Nitric oxide released by neuronal nitric oxide synthase-containing neurons may mediate glutamate-induced excitotoxic cell death, a mechanism proposed to be instrumental in causing the neurodegeneration seen in Huntington's disease. The results described here suggest that although the population of interneurons containing somatostatin, neuropeptide Y and neuronal nitric oxide synthase do survive in the striatum in Huntington's disease they are damaged during the course of the disease. The results also show that the reduction in neuronal nitric oxide synthase and somatostatin messenger RNAs is most pronounced in the more severely affected dorsal regions of the striatum. Furthermore, the loss of neuronal nitric oxide messenger RNA becomes more pronounced with the severity of the disease; thus implying a down-regulation in neuronal nitric oxide synthase messenger RNA synthesis, and potentially neuronal nitric oxide synthase protein levels, in Huntington's disease.
对亨廷顿病患者和对照者的尾状核、壳核及感觉运动皮层中神经元型一氧化氮合酶和生长抑素信使核糖核酸的细胞丰度进行了比较。在亨廷顿病患者中，尾状核和壳核内神经元型一氧化氮合酶信使核糖核酸显著减少，但感觉运动皮层中未减少；随着疾病严重程度增加，神经元型一氧化氮合酶信使核糖核酸的减少更为明显。在亨廷顿病患者中，背侧壳核内生长抑素基因表达显著减少，但在所有其他检查区域基本未变。在病理改变严重的亨廷顿病患者纹状体中，表达可检测水平神经元型一氧化氮合酶信使核糖核酸的神经元密度降低；在对照者和亨廷顿病患者中，表达可检测水平生长抑素信使核糖核酸的神经元密度相似。在疾病的所有阶段，整个纹状体内始终存在神经肽Y、生长抑素和NADPH-黄递酶阳性神经元。在人类纹状体和大脑皮层的中间神经元中，神经元型一氧化氮合酶和NADPH-黄递酶活性（含一氧化氮合酶神经元的一种组织化学标记）与生长抑素和神经肽Y共定位。尽管与亨廷顿病相关的神经变性在纹状体（尤其是背侧区域）最为明显，但神经元型一氧化氮合酶/神经肽Y/生长抑素中间神经元相对未受影响。含神经元型一氧化氮合酶的神经元释放的一氧化氮可能介导谷氨酸诱导的兴奋性毒性细胞死亡，这一机制被认为在导致亨廷顿病所见的神经变性中起作用。此处所述结果表明，尽管在亨廷顿病中，含有生长抑素、神经肽Y和神经元型一氧化氮合酶的中间神经元群体在纹状体中确实存活，但在疾病过程中会受到损害。结果还表明，神经元型一氧化氮合酶和生长抑素信使核糖核酸的减少在纹状体受影响更严重的背侧区域最为明显。此外，随着疾病严重程度增加，神经元型一氧化氮信使核糖核酸的缺失更为明显；因此这意味着在亨廷顿病中，神经元型一氧化氮合酶信使核糖核酸合成以及潜在的神经元型一氧化氮合酶蛋白水平下调。
