Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Saitama, Japan.
Int J Neuropsychopharmacol. 2010 Nov;13(10):1355-68. doi: 10.1017/S1461145710000362. Epub 2010 Apr 15.
We previously reported that neuron-specific mutant Polg1 (mitochondrial DNA polymerase) transgenic (Tg) mice exhibited bipolar disorder (BD)-like phenotypes such as periodic activity change and altered circadian rhythm. In this study, we re-evaluated two datasets resulting from DNA microarray analysis to estimate a biological pathway associated with the disorder. The gene lists were derived from the comparison between post-mortem brains of BD patients and control subjects, and from the comparison between the brains of Tg and wild-type mice. Gene ontology analysis showed that 16 categories overlapped in the altered gene expression profiles of BD patients and the mouse model. In the brains of Tg mice, 33 genes showed similar changes in the frontal cortex and hippocampus compared to wild-type mice. Among the 33 genes, SFPQ and PPIF were differentially expressed in post-mortem brains of BD patients compared to control subjects. The only gene consistently down-regulated in both patients and the mouse model was PPIF, which encodes cyclophilin D (CypD), a component of the mitochondrial permeability transition pore. A blood-brain barrier-permeable CypD inhibitor significantly improved the abnormal behaviour of Tg mice at 40 mg/kg.d. These findings collectively suggest that CypD is a promising target for a new drug for BD.
我们之前曾报道，神经元特异性突变型 Polg1（线粒体 DNA 聚合酶）转基因（Tg）小鼠表现出双相障碍（BD）样表型，如周期性活动变化和昼夜节律改变。在这项研究中，我们重新评估了两个 DNA 微阵列分析数据集，以估计与该疾病相关的生物学途径。基因列表来自 BD 患者和对照死后大脑之间的比较，以及 Tg 小鼠和野生型小鼠大脑之间的比较。基因本体分析表明，BD 患者和小鼠模型中改变的基因表达谱有 16 个类别重叠。在 Tg 小鼠的大脑中，与野生型小鼠相比，前额叶皮层和海马体中有 33 个基因发生了类似的变化。在这 33 个基因中，SFPQ 和 PPIF 在 BD 患者死后大脑中与对照组相比表达不同。在患者和小鼠模型中均一致下调的唯一基因是编码细胞色素 P450 D（CypD）的 PPIF，CypD 是线粒体通透性转换孔的组成部分。一种可穿透血脑屏障的 CypD 抑制剂在 40mg/kg.d 时显著改善了 Tg 小鼠的异常行为。这些发现共同表明 CypD 是 BD 新药的一个有前途的靶点。
