Transcriptome analysis reveals altered cholesterol metabolism during the neurodegeneration in mouse scrapie model
Transcriptome analysis reveals altered cholesterol metabolism during the neurodegeneration in mouse scrapie model
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DOI：
10.1111/j.1471-4159.2007.04566.x
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发表时间：
2007-08-01
影响因子：
4.7
通讯作者：
Kretzschmar, Hans A.
中科院分区：
文献类型：
--
作者：
Xiang, Wei;Hummel, Manuela;Kretzschmar, Hans A.
为了确定朊病毒病发展过程中中枢神经系统的动态转录变化，使用 Affymetrix 微阵列技术对接种前即刻和接种后不同时间点的瘙痒病感染小鼠和年龄匹配的模拟接种对照小鼠的大脑进行了分析。总共 449 个探针组，代表 430 个基因，在一段时间内显示了瘙痒病接种小鼠和模拟接种小鼠之间的差异表达。根据表达模式，这些基因可以分为两簇：与模拟接种的大脑相比，簇 1 中的基因在瘙痒病感染的大脑中表现出较低的 mRNA 水平，而簇 2 中的基因在瘙痒病感染的大脑中表现出较高的 mRNA 水平。差异表达基因的功能分析揭示了受影响最严重的生物过程：胆固醇代谢。胆固醇相关基因的表达模式表明患病大脑中胆固醇合成受到抑制。值得注意的是，随着年龄的增长，许多簇1基因，包括一些胆固醇相关基因，不仅显示出感染瘙痒病的大脑中mRNA水平降低，而且模拟接种大脑中的mRNA水平也随着年龄的增长而增加。对未经治疗的小鼠中一些胆固醇相关基因的定量 RT-PCR 分析表明，在模拟接种的大脑中观察到的检查基因的变化主要与年龄相关。这一发现表明年龄相关基因与痒病相关神经变性之间存在联系。
To identify the dynamic transcriptional alterations in CNS during the development of prion disease, brains of scrapieinfected mice and age-matched, mock-inoculated controls were analyzed immediately before inoculation and at different time points post-inoculation using Affymetrix microarray technique. A total of 449 probe sets, representing 430 genes, showed differential expression between scrapie- and mockinoculated mice over the time course. These genes could be separated into two clusters according to expression patterns: the genes in cluster 1 demonstrated lower mRNA levels in scrapie-infected brains when compared with mock-inoculated brains, whereas genes in cluster 2 showed higher mRNA levels in scrapie-infected brains. Functional analysis of differentially expressed genes revealed the most severely affected biological process: cholesterol metabolism. The expression patterns of the cholesterol-related genes indicated an inhibited cholesterol synthesis in the diseased brains. Conspicuously, a number of cluster 1 genes, including some of cholesterol-related genes, showed not only decreasing mRNA levels in scrapie-infected brains but also increasing mRNA levels in mock-inoculated brains with increasing age. Quantitative RT-PCR analysis of some cholesterol-related genes in untreated mice suggested that changes of the examined genes observed in mock-inoculated brains are mainly age related. This finding indicated a link between agerelated genes and scrapie-associated neurodegeneration.