Augood S J, Faull R L, Love D R, Emson P C
Department of Neurobiology, Babraham Institute, Cambridge, U.K.
Neuroscience. 1996 Jun;72(4):1023-36. doi: 10.1016/0306-4522(95)00595-1.
The expression of enkephalin and substance P messenger RNAs was examined in the caudate-putamen of human post mortem tissue from control and Huntington's disease tissue using in situ hybridization techniques and human specific enkephalin and substance P [35S] oligonucleotides. Macroscopic and microscopic quantification of enkephalin and substance P gene expression was carried out using computer-assisted image analysis. Tissue was collected from six control cases with no sign of neurological disease and six Huntington's disease cases ranging from grades 0 to 3 as determined by neuropathological evaluation. The clinical and pathological diagnosis of Huntington's disease was confirmed unequivocally by genetic analysis of the CAG repeat length in both copies of IT15, the Huntington's disease gene. A marked reduction in both enkephalin and substance P messenger RNAs was detected in all regions of the caudate nucleus and putamen in Huntington's disease grades 2/3 when compared to controls; in the dorsal caudate few enkephalin or substance P messenger RNA-positive cells were detected. For the early grade (0/1) Huntington's disease cases, a heterogeneous reduction in both enkephalin and substance P messenger RNAs were noted; for enkephalin messenger RNA the striatal autoradiograms displayed a conspicuous patchy appearance. Detailed cellular analysis of the dorsal caudate revealed a striking reduction in the number of enkephalin and substance P messenger RNA-positive cells detected and in the intensity of hybridization signal/cell. These data suggest that both the "indirect" GABA/enkephalin and "direct" GABA/substance P pathways are perturbed very early in the course of the disease and that these early changes in chemical signalling may possibly underlie the onset of clinical symptoms.
运用原位杂交技术以及人特异性脑啡肽和P物质[35S]寡核苷酸，对来自对照和亨廷顿病患者死后脑组织的尾状核 - 壳核中脑啡肽和P物质信使核糖核酸的表达进行了检测。采用计算机辅助图像分析对脑啡肽和P物质基因表达进行宏观和微观定量。从6例无神经疾病迹象的对照病例以及6例经神经病理学评估确定为0至3级的亨廷顿病病例中采集组织。通过对亨廷顿病基因IT15两个拷贝中CAG重复长度的基因分析，明确证实了亨廷顿病的临床和病理诊断。与对照相比，在亨廷顿病2/3级患者的尾状核和壳核所有区域中，均检测到脑啡肽和P物质信使核糖核酸显著减少；在背侧尾状核中，几乎未检测到脑啡肽或P物质信使核糖核酸阳性细胞。对于早期（0/1级）亨廷顿病病例，脑啡肽和P物质信使核糖核酸均出现异质性减少；脑啡肽信使核糖核酸的纹状体放射自显影片呈现出明显的斑片状外观。对背侧尾状核的详细细胞分析显示，检测到的脑啡肽和P物质信使核糖核酸阳性细胞数量以及杂交信号/细胞强度均显著降低。这些数据表明，“间接”GABA/脑啡肽和“直接”GABA/P物质通路在疾病进程的早期就受到干扰，并且这些化学信号的早期变化可能是临床症状发作的基础。
