Hwang Daehee, Lee Inyoul Y, Yoo Hyuntae, Gehlenborg Nils, Cho Ji-Hoon, Petritis Brianne, Baxter David, Pitstick Rose, Young Rebecca, Spicer Doug, Price Nathan D, Hohmann John G, Dearmond Stephen J, Carlson George A, Hood Leroy E
Institute for Systems Biology, Seattle, WA 98103, USA.
Mol Syst Biol. 2009;5:252. doi: 10.1038/msb.2009.10. Epub 2009 Mar 24.
Prions cause transmissible neurodegenerative diseases and replicate by conformational conversion of normal benign forms of prion protein (PrP(C)) to disease-causing PrP(Sc) isoforms. A systems approach to disease postulates that disease arises from perturbation of biological networks in the relevant organ. We tracked global gene expression in the brains of eight distinct mouse strain-prion strain combinations throughout the progression of the disease to capture the effects of prion strain, host genetics, and PrP concentration on disease incubation time. Subtractive analyses exploiting various aspects of prion biology and infection identified a core of 333 differentially expressed genes (DEGs) that appeared central to prion disease. DEGs were mapped into functional pathways and networks reflecting defined neuropathological events and PrP(Sc) replication and accumulation, enabling the identification of novel modules and modules that may be involved in genetic effects on incubation time and in prion strain specificity. Our systems analysis provides a comprehensive basis for developing models for prion replication and disease, and suggests some possible therapeutic approaches.
朊病毒可引发可传播的神经退行性疾病,并通过将正常良性形式的朊病毒蛋白(PrP(C))构象转化为致病的PrP(Sc)异构体来进行复制。一种疾病系统方法假定疾病源于相关器官中生物网络的扰动。我们在疾病进展过程中追踪了八种不同小鼠品系 - 朊病毒株组合的大脑中的全局基因表达,以捕捉朊病毒株、宿主遗传学和PrP浓度对疾病潜伏期的影响。利用朊病毒生物学和感染的各个方面进行的消减分析确定了333个差异表达基因(DEG)的核心,这些基因似乎是朊病毒疾病的核心。差异表达基因被映射到反映特定神经病理事件以及PrP(Sc)复制和积累的功能途径和网络中,从而能够识别可能参与对潜伏期的遗传效应和朊病毒株特异性的新模块。我们的系统分析为开发朊病毒复制和疾病模型提供了全面的基础,并提出了一些可能的治疗方法。