Department of Molecular Pathogenesis and Genetics, Veterinary Laboratories Agency, Surrey, United Kingdom.
PLoS One. 2010 Dec 3;5(12):e14207. doi: 10.1371/journal.pone.0014207.
Bovine spongiform encephalopathy (BSE) is a fatal, transmissible, neurodegenerative disease of cattle. To date, the disease process is still poorly understood. In this study, brain tissue samples from animals naturally infected with BSE were analysed to identify differentially regulated genes using Affymetrix GeneChip Bovine Genome Arrays. A total of 230 genes were shown to be differentially regulated and many of these genes encode proteins involved in immune response, apoptosis, cell adhesion, stress response and transcription. Seventeen genes are associated with the endoplasmic reticulum (ER) and 10 of these 17 genes are involved in stress related responses including ER chaperones, Grp94 and Grp170. Western blotting analysis showed that another ER chaperone, Grp78, was up-regulated in BSE. Up-regulation of these three chaperones strongly suggests the presence of ER stress and the activation of the unfolded protein response (UPR) in BSE. The occurrence of ER stress was also supported by changes in gene expression for cytosolic proteins, such as the chaperone pair of Hsp70 and DnaJ. Many genes associated with the ubiquitin-proteasome pathway and the autophagy-lysosome system were differentially regulated, indicating that both pathways might be activated in response to ER stress. A model is presented to explain the mechanisms of prion neurotoxicity using these ER stress related responses. Clustering analysis showed that the differently regulated genes found from the naturally infected BSE cases could be used to predict the infectious status of the samples experimentally infected with BSE from the previous study and vice versa. Proof-of-principle gene expression biomarkers were found to represent BSE using 10 genes with 94% sensitivity and 87% specificity.
牛海绵状脑病（BSE）是一种致命的、可传播的、牛的神经退行性疾病。迄今为止，该疾病的发病机制仍知之甚少。在这项研究中，使用 Affymetrix GeneChip Bovine Genome Arrays 分析了自然感染 BSE 的动物的脑组织样本，以鉴定差异调节基因。结果显示共有 230 个基因差异调节，其中许多基因编码参与免疫反应、细胞凋亡、细胞黏附、应激反应和转录的蛋白质。17 个基因与内质网（ER）相关，这 17 个基因中有 10 个参与应激相关反应，包括 ER 伴侣蛋白、Grp94 和 Grp170。Western blotting 分析显示，另一种 ER 伴侣蛋白 Grp78 在 BSE 中上调。这三种伴侣蛋白的上调强烈表明 ER 应激的存在和未折叠蛋白反应（UPR）在 BSE 中的激活。内质网应激的发生也得到了细胞质蛋白基因表达变化的支持，如伴侣蛋白对 Hsp70 和 DnaJ。许多与泛素-蛋白酶体途径和自噬-溶酶体系统相关的基因也差异调节，表明这两种途径可能都被激活以应对 ER 应激。提出了一个模型，使用这些与 ER 应激相关的反应来解释朊病毒神经毒性的机制。聚类分析表明，从自然感染的 BSE 病例中发现的差异调节基因可用于预测之前研究中用 BSE 实验感染的样本的感染状态，反之亦然。使用 10 个基因，灵敏度为 94%，特异性为 87%，找到了代表 BSE 的原理验证基因表达生物标志物。
