Quantitative analysis of mitochondrial DNA deletions in the brains of patients with bipolar disorder and schizophrenia
Quantitative analysis of mitochondrial DNA deletions in the brains of patients with bipolar disorder and schizophrenia
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DOI：
10.1017/s1461145705005213
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发表时间：
2005-12-01
影响因子：
4.8
通讯作者：
Kato, T
中科院分区：
文献类型：
--
作者：
Kakiuchi, C;Ishiwata, M;Kato, T
几项临床、遗传和神经成像研究表明，线粒体功能障碍与双相情感障碍和精神分裂症的病理生理学有关。据报道，线粒体DNA(MtDNA)4977个碱基的缺失，即所谓的“常见缺失”，与这两种精神疾病有关。这种缺失在精神分裂症中缺乏正常的年龄相关性积累，在双相情感障碍中常见缺失的发生率增加。然而，即使在受影响的双相样本中，共同缺失的水平也相对较小，表明共同缺失对呼吸功能没有起到病理生理作用。我们假设，多个mtDNA缺失的累积，而不是共同的缺失，参与了这两个主要精神障碍的病理生理学。为了验证这一假说，我们通过比较84名受试者(30名对照组，27名双相情感障碍患者和27名精神分裂症患者)额叶皮质线粒体DNA中两个稀土离子ND1和ND4的拷贝数来评估线粒体DNA缺失(S)。我们还评估了线粒体DNA与核DNA的相对数量以及参与复制线粒体DNA的DNA聚合酶伽马(Polg)的表达水平。我们没有观察到mtDNA缺失与额叶皮质两种主要精神障碍之间的联系，这并不支持我们的假设。然而，我们做了以下观察，尽管经Bonferroni校正后没有显著差异：(1)女性精神分裂症患者线粒体DNA/核DNA的比率显著高于对照组(p=0.040)；(2)在双相情感障碍患者中，线粒体DNA的相对数量随着年龄的增长而下降(p=0.016)。此外，Polg的表达在双相情感障碍中显著上调(p=0.036)。我们的结果表明，维持线粒体DNA复制的系统异常可能是双相情感障碍和精神分裂症的原因。
Several clinical, genetic and neuromaging studies implicate mitochondrial dysfunction in the pathophysiology of bipolar disorder and schizophrenia. It has been reported that a mitochondrial DNA (mtDNA) deletion of 4977 bp, known as the 'common deletion', is associated with both mental illnesses. A lack of normal age-related accumulation of this deletion in schizophrenia and increased occurrence of the common deletion in bipolar disorder have been reported. However, even in the affected bipolar samples, the levels of common deletion were relatively small, indicating that the common deletion did not play a pathophysiological role in respiratory function. We hypothesized that accumulation of multiple mtDNA deletions, rather than the common deletion alone, is involved in the pathophysiology of these two major mental disorders. To test this hypothesis, we assessed mtDNA deletion(s) by comparing the copy number of two re-ions in mtDNA - ND1 and ND4 - using real-time quantitative PCR in the frontal cortex of 84 subjects (30 control, 27 with bipolar disorder, and 27 with schizophrenia). We also assessed the relative amount of mtDNA vs. nuclear DNA and the expression level of DNA polymerase gamma (POLG), which is involved in replicating mtDNA. We observed no association between mtDNA deletions and the two major mental disorders in the frontal cortex, which did not support our hypothesis. We did, however, make the following observations, although they were not significant after Bonferroni correction: (1) the ratio of mtDNA to nuclear DNA was significantly higher in female patients with schizophrenia than in control females (p =0.040) and (2) in bipolar disorder, the relative amount of mtDNA decreased with age (p = 0.016). Furthermore, POLG expression was significantly up-regulated in bipolar disorder (p = 0.036). Our results suggest that abnormalities in the system maintaining replication of mtDNA may underlie bipolar disorder and schizophrenia.