MRC Prion Unit and Department of Neurodegenerative Diseases, UCL Institute of Neurology, University College, London, United Kingdom.
PLoS One. 2010 Dec 6;5(12):e15019. doi: 10.1371/journal.pone.0015019.
In neurodegenerative conditions such as Alzheimer's and prion disease it has been shown that host genetic background can have a significant effect on susceptibility. Indeed, human genome-wide association studies (GWAS) have implicated several candidate genes. Understanding such genetic susceptibility is relevant to risks of developing variant CJD (vCJD) in populations exposed to bovine spongiform encephalopathy (BSE) and understanding mechanisms of neurodegeneration. In mice, aspects of prion disease susceptibility can be modelled by examining the incubation period following experimental inoculation. Quantitative trait linkage studies have already identified multiple candidate genes; however, it is also possible to take an individual candidate gene approach. Rarb and Stmn2 were selected as candidates based on the known association with vCJD. Because of the increasing overlap described between prion and Alzheimer's diseases we also chose Clu, Picalm and Cr1, which were identified as part of Alzheimer's disease GWAS. Clusterin (Clu) was considered to be of particular interest as it has already been implicated in prion disease. Approximately 1,000 heterogeneous stock (HS) mice were inoculated intra-cerebrally with Chandler/RML prions and incubation times were recorded. Candidate genes were evaluated by sequencing the whole transcript including exon-intron boundaries and potential promoters in the parental lines of the HS mice. Representative SNPs were genotyped in the HS mice. No SNPs were identified in Cr1 and no statistical association with incubation time was seen for Clu (P = 0.96) and Picalm (P = 0.91). Significant associations were seen for both Stmn2 (P = 0.04) and Rarb (P = 0.0005), however, this was only highly significant for Rarb. This data provides significant further support for a role for the Rarb region of Mmu14 and Stmn2 in prion disease.
在神经退行性疾病如阿尔茨海默病和朊病毒病中，已经表明宿主遗传背景对易感性有显著影响。事实上，人类全基因组关联研究（GWAS）已经涉及了几个候选基因。了解这种遗传易感性与接触牛海绵状脑病（BSE）的人群中变异型克雅氏病（vCJD）的发病风险以及理解神经退行性机制相关。在小鼠中，可以通过检查实验接种后的潜伏期来模拟朊病毒病易感性的某些方面。定量性状连锁研究已经确定了多个候选基因；然而，也可以采用单个候选基因方法。Rarb 和 Stmn2 被选为候选基因，是基于它们与 vCJD 的已知关联。由于描述的朊病毒病和阿尔茨海默病之间的重叠越来越多，我们还选择了 Clu、Picalm 和 Cr1，它们被确定为阿尔茨海默病 GWAS 的一部分。载脂蛋白（Clu）被认为特别有趣，因为它已经与朊病毒病有关。大约 1000 只异质 stock (HS) 小鼠被用 Chandler/RML 朊病毒颅内接种，并记录潜伏期。通过对 HS 小鼠的亲本系进行全转录测序，包括外显子-内含子边界和潜在启动子，评估候选基因。在 HS 小鼠中对代表性 SNP 进行了基因分型。在 Cr1 中未发现 SNP，在 Clu（P=0.96）和 Picalm（P=0.91）中与潜伏期也没有统计学关联。Stmn2（P=0.04）和 Rarb（P=0.0005）都存在显著关联，但 Rarb 的关联度非常显著。这一数据为 Rarb 区域 Mmu14 和 Stmn2 在朊病毒病中的作用提供了进一步的重要支持。
