Transcriptomic Responses to Prion Disease in Rats

While prion infections have been extensively characterized in the laboratory mouse, little is known regarding the molecular responses to prions in other rodents. To explore these responses and make comparisons, we generated a prion disease in the laboratory rat by successive passage of mouse RML prions. Here we describe the accumulation of prions and associated pathology in the rat and describe the transcriptional impact throughout prion disease. Comparative transcriptional profiling between laboratory mice and rats suggests that similar molecular processes are unfolding in response to prion infection. At the level of individual transcripts, however, variability exists between mice and rats and many genes deregulated in mouse scrapie are not affected in rats. Notwithstanding these differences, many transcriptome responses are conserved between mice and rats infected with scrapie. Our findings highlight the usefulness of comparative approaches to understanding neurodegeneration and prion diseases in particular. We Adapted RML Mouse Scrapie into Rats and measured the resulting gene expression changes in brain as a result of disease progression. Rats were infected by intracranial inoculation with prion isolates obtained by adaptation of mouse RML scrapie prions into rats. Brain samples were collected from third and fourth passage infected rats and age-matched controls at specified timepoints and gene expression profiles obtained. For each time point, 3 diseased and control brain samples were profiled.

尽管实验室小鼠的朊病毒（prion）感染已在实验室中得到广泛表征，但学界对其他啮齿类动物针对朊病毒的分子应答仍知之甚少。为探究此类应答并开展对比研究，我们通过连续传代小鼠RML朊病毒，在实验大鼠中诱导出朊病毒疾病。本研究阐述了大鼠体内朊病毒的积累与相关病理特征，并解析了整个朊病毒疾病进程中的转录影响。实验室小鼠与大鼠的对比转录谱分析显示，二者在朊病毒感染后激活的分子进程具有相似性。然而在单个转录本（transcript）层面，小鼠与大鼠间存在差异：许多在小鼠痒病（scrapie）中失调的基因在大鼠体内并未受到影响。尽管存在上述差异，感染痒病的小鼠与大鼠间仍有诸多转录组应答特征是保守的。本研究结果凸显了比较研究方法在解析神经退行性疾病，尤其是朊病毒疾病方面的应用价值。我们将RML小鼠痒病模型适配至大鼠体内，并检测了疾病进程中大鼠大脑的基因表达变化。大鼠通过颅内接种适配至大鼠的小鼠RML痒病朊病毒分离株实现感染。在指定时间点，分别采集第三代、第四代感染大鼠以及年龄匹配对照组大鼠的脑组织样本，并获取其基因表达谱。每个时间点均设置3份感染组与3份对照组脑组织样本用于表达谱分析。