Therapeutic implications of down-regulation of cyclophilin D in bipolar disorder
Therapeutic implications of down-regulation of cyclophilin D in bipolar disorder
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DOI：
10.1017/s1461145710000362
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发表时间：
2010-11-01
影响因子：
4.8
通讯作者：
Kato, Tadafumi
中科院分区：
文献类型：
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作者：
Kubota, Mie;Kasahara, Takaoki;Kato, Tadafumi
我们之前报道过神经元特异性突变体Polg1（线粒体DNA聚合酶）转基因（Tg）小鼠表现出双相情感障碍（BD）样表型，如周期性活动改变和昼夜节律改变。在这项研究中，我们重新评估了DNA微阵列分析产生的两个数据集，以估计与该疾病相关的生物学途径。基因表来源于BD患者死后脑与对照组的比较，以及Tg与野生型小鼠脑的比较。基因本体论分析显示，BD患者与小鼠模型基因表达谱的改变有16类重叠。在Tg小鼠的大脑中，有33个基因在额叶皮层和海马体中显示出与野生型小鼠相似的变化。在33个基因中，SFPQ和PPIF在BD患者死后大脑中的表达与对照组相比存在差异。唯一在患者和小鼠模型中持续下调的基因是PPIF，它编码亲环蛋白D (CypD)，这是线粒体通透性过渡孔的一个组成部分。可通过血脑屏障的CypD抑制剂在40mg /kg.d时可显著改善Tg小鼠的异常行为。这些发现共同表明CypD是一种治疗双相障碍的新药的有希望的靶点。
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.