ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2008; 4(4):223-235. doi:10.7150/ijbs.4.223 This issue Cite
Research Paper
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
1. Department of Biochemistry and Molecular Biology and the Catherine Birch McCormick Genomics Center, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037
2. Department of Psychiatry and Center for the Study of Traumatic Stress, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
3. Division of Hematology, Center for Biological Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
4. Stanley Medical Research Institute, Chevy Chase, MD 20894
5. Laboratory of Clinical Genomics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
Abstract
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.
Keywords: PTSD, Brain dorsolateral prefrontal cortex BA46, Gene expression pattern, Biomarker, Mitochondria, Canonical pathways, Molecular networks, Neuropsychiatric drug targets
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