Dysregulated mitochondrial genes and networks with drug targets in postmortem brain of patients with posttraumatic stress disorder (PTSD) revealed by human mitochondria-focused cDNA microarrays.
Dysregulated mitochondrial genes and networks with drug targets in postmortem brain of patients with posttraumatic stress disorder (PTSD) revealed by human mitochondria-focused cDNA microarrays.
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DOI：
10.7150/ijbs.4.223
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发表时间：
2008-08-05
影响因子：
9.2
通讯作者：
Ursano RJ
中科院分区：
文献类型：
--
作者：
Su YA;Wu J;Zhang L;Zhang Q;Su DM;He P;Wang BD;Li H;Webster MJ;Traumatic Stress Brain Study Group;Rennert OM;Ursano RJ
创伤后应激障碍（PTSD）与背外侧前额叶皮层（DLPFC）活动减少有关，DLPFC是调节工作记忆和恐惧反应的准备和选择的大脑区域。我们使用人类线粒体聚焦cDNA芯片研究了死后PTSD患者（n=6）和非PTSD患者（n=6） DLPFC Brodmann区（BA） 46的基因表达谱。我们的研究发现，在所有12个BA46样本中，有800个线粒体聚焦基因的PTSD特异性表达指纹，在PTSD和对照样本中，有119个（±>1.25,p<0.05）和42个（±>1.60,p<0.05）基因失调。定量RT-PCR验证了芯片结果。这些指纹基本上可以将PTSD患者的DLPFC BA46大脑与对照组区分开来。119个基因中，与线粒体功能障碍（4.8%,p=6.61 × 10-6）、氧化磷酸化（3.8%,p=9.04 × 10-4）、细胞存活-凋亡（25.2%,p<0.05）和神经系统疾病（23.5%,p<0.05）相关的基因比例最高（±125%,p<0.05）。50（50）个失调基因存在于已知参与神经元功能存活的分子网络中，并包含7个神经精神药物靶点。三十（30）个失调基因与许多神经精神疾病有关。我们的研究结果表明，PTSD DLPFC BA46存在线粒体功能障碍，并提供了可能最终作为PTSD诊断的生物标志物的表达指纹，以及可能证明有助于开发预防和治疗PTSD的药物和分子靶点。
Posttraumatic stress disorder (PTSD) is associated with decreased activity in the dorsolateral prefrontal cortex (DLPFC), the brain region that regulates working memory and preparation and selection of fear responses. We investigated gene expression profiles in DLPFC Brodmann area (BA) 46 of postmortem patients with (n=6) and without PTSD (n=6) using human mitochondria-focused cDNA microarrays. Our study revealed PTSD-specific expression fingerprints of 800 informative mitochondria-focused genes across all of these 12 BA46 samples, and 119 (±>1.25, p<0.05) and 42 (±>1.60, p<0.05) dysregulated genes between the PTSD and control samples. Quantitative RT-PCR validated the microarray results. These fingerprints can essentially distinguish the PTSD DLPFC BA46 brains from controls. Of the 119 dysregulated genes (±≥125%, p<0.05), the highest percentages were associated with mitochondrial dysfunction (4.8%, p=6.61x10-6), oxidative phosphorylation (3.8%, p=9.04x10-4), cell survival-apoptosis (25.2%, p<0.05) and neurological diseases (23.5%, p<0.05). Fifty (50) dysregulated genes were present in the molecular networks that are known to be involved in neuronal function-survival and contain 7 targets for neuropsychiatric drugs. Thirty (30) of the dysregulated genes are associated with a number of neuropsychiatric disorders. Our results indicate mitochondrial dysfunction in the PTSD DLPFC BA46 and provide the expression fingerprints that may ultimately serve as biomarkers for PTSD diagnosis and the drugs and molecular targets that may prove useful for development of remedies for prevention and treatment of PTSD.