Department of Physiology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.
PLoS One. 2012;7(4):e33923. doi: 10.1371/journal.pone.0033923. Epub 2012 Apr 10.
The minor allele of rs11136000 within CLU is strongly associated with reduced Alzheimer's disease (AD) risk. The mechanism underlying this association is unclear. Here, we report that CLU1 and CLU2 are the two primary CLU isoforms in human brain; CLU1 and CLU2 share exons 2-9 but differ in exon 1 and proximal promoters. The expression of both CLU1 and CLU2 was increased in individuals with significant AD neuropathology. However, only CLU1 was associated with the rs11136000 genotype, with the minor "protective" rs11136000T allele being associated with increased CLU1 expression. Since CLU1 and CLU2 are predicted to encode intracellular and secreted proteins, respectively, we compared their expression; for both CLU1 and CLU2 transfected cells, clusterin is present in the secretory pathway, accumulates in the extracellular media, and is similar in size to clusterin in human brain. Overall, we interpret these results as indicating that the AD-protective minor rs11136000T allele is associated with increased CLU1 expression. Since CLU1 and CLU2 appear to produce similar proteins and are increased in AD, the AD-protection afforded by the rs11136000T allele may reflect increased soluble clusterin throughout life.
CLU 基因 rs11136000 的次要等位基因与阿尔茨海默病（AD）风险降低显著相关。其相关机制尚不清楚。在此，我们报告 CLU1 和 CLU2 是人类大脑中 CLU 的两种主要异构体；CLU1 和 CLU2 共享外显子 2-9，但在 1 号外显子和近端启动子上存在差异。在具有明显 AD 神经病理学的个体中，CLU1 和 CLU2 的表达均增加。然而，只有 CLU1 与 rs11136000 基因型相关，次要的“保护性”rs11136000T 等位基因与 CLU1 表达增加相关。由于 CLU1 和 CLU2 分别预测为细胞内和分泌蛋白，因此我们比较了它们的表达；对于转染了 CLU1 和 CLU2 的细胞，簇集素存在于分泌途径中，在细胞外培养基中积累，并且大小与人类大脑中的簇集素相似。总的来说，我们将这些结果解释为表明 AD 保护性的次要 rs11136000T 等位基因与 CLU1 表达增加相关。由于 CLU1 和 CLU2 似乎产生相似的蛋白质，并且在 AD 中增加，rs11136000T 等位基因提供的 AD 保护可能反映了整个生命周期中可溶性簇集素的增加。
