Expression data for inbred mouse brains

Prion diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. In order to test this hypothesis we combined incubation time data from five different inbred lines of mice with quantitative gene expression profiling in normal brains and identified five genes with expression levels that correlate with incubation time. One of these genes, Hspa13 (Stch), is a member of the Hsp70 family of ATPase heat shock proteins which have been previously implicated in prion propagation. To test whether Hspa13 plays a causal role in determining the incubation period we tested two over-expressing mouse models. The Tc1 human chromosome 21 (Hsa21) transchromosomic mouse model of Down syndrome is trisomic for many Hsa21 genes including Hspa13 and following Chandler/RML prion inoculation shows a 4% reduction in incubation time. Furthermore, a transgenic model with eight fold over-expression of mouse Hspa13 exhibited highly significant reductions in incubation time of 16%, 15% and 7% following infection with Chandler/RML, ME7 and MRC2 prion strains respectively. These data further implicate Hsp70-like molecular chaperones in protein misfolding disorders such as prion disease. 5 inbred lines of mice, 5 samples for each line朊病毒疾病（Prion diseases）是一类致命性神经退行性疾病，涵盖动物中的牛海绵状脑病（BSE，bovine spongiform encephalopathy）、羊瘙痒症，以及人类的克雅氏病（CJD，Creutzfeldt-Jakob disease）。此类疾病具有较长的潜伏期，其潜伏期差异由包括遗传背景在内的多种因素决定。在部分病例中，潜伏期或可与基因表达水平直接相关。为验证这一假说，本研究整合了5种不同近交系小鼠的潜伏期数据与正常脑组织的定量基因表达谱分析结果，最终筛选出5个表达水平与潜伏期相关的基因。其中，Hspa13（又名Stch）属于ATP酶热休克蛋白70（Hsp70）家族，该家族此前已被证实与朊病毒增殖过程相关。为验证Hspa13在调控潜伏期过程中是否发挥因果作用，本研究测试了两种Hspa13过表达小鼠模型：唐氏综合征的Tc1人21号染色体（Hsa21）转染色体小鼠模型携带包括Hspa13在内的多个Hsa21基因的三拷贝，在接种Chandler/RML朊病毒毒株后，其潜伏期缩短了4%；此外，小鼠Hspa13八倍过表达的转基因模型，在分别感染Chandler/RML、ME7及MRC2朊病毒毒株后，潜伏期分别显著缩短16%、15%与7%。上述实验数据进一步表明，类似Hsp70的分子伴侣蛋白参与了朊病毒病这类蛋白质错误折叠疾病的病理进程。本研究涉及5种近交系小鼠，每个品系包含5个样本。