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Mitochondria-focused gene expression profile reveals common pathways and CPT1B dysregulation in both rodent stress model and human subjects with PTSD.

Zhang L, Li H, Hu X, Benedek DM, Fullerton CS, Forsten RD, Naifeh JA, Li X, Wu H, Benevides KN, Le T, Smerin S, Russell DW, Ursano RJ - Transl Psychiatry (2015)

Bottom Line: Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain.This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala.Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result.

View Article: PubMed Central - PubMed

Affiliation: Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

ABSTRACT
Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain. However, the biologic approach to identifying the mitochondria-focused genes underlying the pathogenesis of PTSD is still in its infancy. Previous research, using a human mitochondria-focused cDNA microarray (hMitChip3) found dysregulated mitochondria-focused genes present in postmortem brains of PTSD patients, indicating that those genes might be PTSD-related biomarkers. To further test this idea, this research examines profiles of mitochondria-focused gene expression in the stressed-rodent model (inescapable tail shock in rats), which shows characteristics of PTSD-like behaviors and also in the blood of subjects with PTSD. This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala. Ten common pathways, including fatty acid metabolism and peroxisome proliferator-activated receptors (PPAR) pathways were dysregulated in the amygdala of the stressed rats. Carnitine palmitoyltransferase 1B (CPT1B), an enzyme in the fatty acid metabolism and PPAR pathways, was significantly over-expressed in the amygdala (P < 0.007) and in the blood (P < 0.01) of stressed rats compared with non-stressed controls. In human subjects with (n = 28) or without PTSD (n = 31), significant over-expression of CPT1B in PTSD was also observed in the two common dysregulated pathways: fatty acid metabolism (P = 0.0027, false discovery rate (FDR) = 0.043) and PPAR (P = 0.006, FDR = 0.08). Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result. These findings indicate that blood can be used as a specimen in the search for PTSD biomarkers in fatty acid metabolism and PPAR pathways, and, in addition, that CPT1B may contribute to the pathology of PTSD.

No MeSH data available.


Related in: MedlinePlus

Box plots of expression data before and after normalization. The quintile normalization algorithms were used to adjust the values of the background-subtracted mean pixel intensities of each and every set of 800 genes that were selected from the hMitChip3 triplicate microarray experiments hybridized with PTSD and control prefrontal cortex RNA samples, as described previously.4 In contrast to the pre-normalization boxplots (top panel), the post-normalized boxplots distribute in the same intervals with the same density center, indicating successful adjustment of data. The post-normalized data were used for clustering analysis. PTSD, posttraumatic stress disorder.
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fig2: Box plots of expression data before and after normalization. The quintile normalization algorithms were used to adjust the values of the background-subtracted mean pixel intensities of each and every set of 800 genes that were selected from the hMitChip3 triplicate microarray experiments hybridized with PTSD and control prefrontal cortex RNA samples, as described previously.4 In contrast to the pre-normalization boxplots (top panel), the post-normalized boxplots distribute in the same intervals with the same density center, indicating successful adjustment of data. The post-normalized data were used for clustering analysis. PTSD, posttraumatic stress disorder.

Mentions: In human subjects, total RNA samples were extracted from blood of subjects with or without PTSD and labeled for triplicate microarray experiments using our recently developed third-generation microarray hMitChip3. Table 2 shows the diagrammatic information about the subjects with PTSD and without PTSD, including their age, sex and ethnicity. To avoid misclassification, the hMitChip3 genes were all measured nine times (three identical probes per microarray and three microarray experiments per specimen), which generated reliable expression data for further analysis.4 The microarray data of 610 740 spots across all 531 gene chips used for 59 RNA samples were filtered by uniform statistic and bioinformatic criteria described previously,27, 28 which generated 591 genes with informative expression profiles. Figure 2 shows the boxplots of mRNA levels of 1170 genes before and after the data normalization. The normalized data were used for unsupervised clustering analysis and visualization (Figure 3). The resultant dendrograms for the sets of genes are indicated in Figures 3 and 4.


Mitochondria-focused gene expression profile reveals common pathways and CPT1B dysregulation in both rodent stress model and human subjects with PTSD.

Zhang L, Li H, Hu X, Benedek DM, Fullerton CS, Forsten RD, Naifeh JA, Li X, Wu H, Benevides KN, Le T, Smerin S, Russell DW, Ursano RJ - Transl Psychiatry (2015)

Box plots of expression data before and after normalization. The quintile normalization algorithms were used to adjust the values of the background-subtracted mean pixel intensities of each and every set of 800 genes that were selected from the hMitChip3 triplicate microarray experiments hybridized with PTSD and control prefrontal cortex RNA samples, as described previously.4 In contrast to the pre-normalization boxplots (top panel), the post-normalized boxplots distribute in the same intervals with the same density center, indicating successful adjustment of data. The post-normalized data were used for clustering analysis. PTSD, posttraumatic stress disorder.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490278&req=5

fig2: Box plots of expression data before and after normalization. The quintile normalization algorithms were used to adjust the values of the background-subtracted mean pixel intensities of each and every set of 800 genes that were selected from the hMitChip3 triplicate microarray experiments hybridized with PTSD and control prefrontal cortex RNA samples, as described previously.4 In contrast to the pre-normalization boxplots (top panel), the post-normalized boxplots distribute in the same intervals with the same density center, indicating successful adjustment of data. The post-normalized data were used for clustering analysis. PTSD, posttraumatic stress disorder.
Mentions: In human subjects, total RNA samples were extracted from blood of subjects with or without PTSD and labeled for triplicate microarray experiments using our recently developed third-generation microarray hMitChip3. Table 2 shows the diagrammatic information about the subjects with PTSD and without PTSD, including their age, sex and ethnicity. To avoid misclassification, the hMitChip3 genes were all measured nine times (three identical probes per microarray and three microarray experiments per specimen), which generated reliable expression data for further analysis.4 The microarray data of 610 740 spots across all 531 gene chips used for 59 RNA samples were filtered by uniform statistic and bioinformatic criteria described previously,27, 28 which generated 591 genes with informative expression profiles. Figure 2 shows the boxplots of mRNA levels of 1170 genes before and after the data normalization. The normalized data were used for unsupervised clustering analysis and visualization (Figure 3). The resultant dendrograms for the sets of genes are indicated in Figures 3 and 4.

Bottom Line: Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain.This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala.Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result.

View Article: PubMed Central - PubMed

Affiliation: Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

ABSTRACT
Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain. However, the biologic approach to identifying the mitochondria-focused genes underlying the pathogenesis of PTSD is still in its infancy. Previous research, using a human mitochondria-focused cDNA microarray (hMitChip3) found dysregulated mitochondria-focused genes present in postmortem brains of PTSD patients, indicating that those genes might be PTSD-related biomarkers. To further test this idea, this research examines profiles of mitochondria-focused gene expression in the stressed-rodent model (inescapable tail shock in rats), which shows characteristics of PTSD-like behaviors and also in the blood of subjects with PTSD. This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala. Ten common pathways, including fatty acid metabolism and peroxisome proliferator-activated receptors (PPAR) pathways were dysregulated in the amygdala of the stressed rats. Carnitine palmitoyltransferase 1B (CPT1B), an enzyme in the fatty acid metabolism and PPAR pathways, was significantly over-expressed in the amygdala (P < 0.007) and in the blood (P < 0.01) of stressed rats compared with non-stressed controls. In human subjects with (n = 28) or without PTSD (n = 31), significant over-expression of CPT1B in PTSD was also observed in the two common dysregulated pathways: fatty acid metabolism (P = 0.0027, false discovery rate (FDR) = 0.043) and PPAR (P = 0.006, FDR = 0.08). Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result. These findings indicate that blood can be used as a specimen in the search for PTSD biomarkers in fatty acid metabolism and PPAR pathways, and, in addition, that CPT1B may contribute to the pathology of PTSD.

No MeSH data available.


Related in: MedlinePlus