Differential expression of gene co-expression networks related to the mTOR signaling pathway in bipolar disorder
Abstract Bipolar disorder (BPD) is a severe mental illness characterized by episodes of depression and mania. To investigate the molecular mechanisms underlying the pathophysiology of bipolar disorder, we performed transcriptome studies using RNA-seq data from the prefrontal cortex (PFC) of individu...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-05-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-022-01944-8 |
| _version_ | 1828344324522246144 |
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| author | Sung Woo Park Mi Kyoung Seo Maree J. Webster Jung Goo Lee Sanghyeon Kim |
| author_facet | Sung Woo Park Mi Kyoung Seo Maree J. Webster Jung Goo Lee Sanghyeon Kim |
| author_sort | Sung Woo Park |
| collection | DOAJ |
| description | Abstract Bipolar disorder (BPD) is a severe mental illness characterized by episodes of depression and mania. To investigate the molecular mechanisms underlying the pathophysiology of bipolar disorder, we performed transcriptome studies using RNA-seq data from the prefrontal cortex (PFC) of individuals with BPD and matched controls, as well as data from cell culture and animal model studies. We found 879 differentially expressed genes that were also replicated in an independent cohort of post-mortem samples. Genes involving the mechanistic target of rapamycine (mTOR) pathway were down-regulated, while genes interrelated with the mTOR pathway such as Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway were up-regulated. Gene co-expression network analyses identified a module related to the mTOR pathway that was up-regulated in BPD and also enriched for markers of endothelial cells. We also found a down-regulated co-expression module enriched for genes involved in mTOR signalling and in mTOR related pathways and enriched with neuronal markers. The mTOR related modules were also replicated in the independent cohort of samples. To investigate whether the expression of the modules related to mTOR signalling pathway could be differentially regulated in different cell types we performed comparative network analyses in experimental models. We found both up-regulated modules in the PFC significantly overlapped with an up-regulated module in the brain endothelial cells from mice treated with lipopolysaccharides (LPS) and mTOR related pathways such as JAK-STAT, PI3K-Akt and ribosome were enriched in the common genes. In addition, the down-regulated module in the PFC significantly overlapped with a down-regulated module from neurons treated with the mTOR inhibitor, Torin1 and mTOR signalling, autophagy, and synaptic vesicle cycles were significantly enriched in the common genes. These results suggest that co-expression networks related to mTOR signalling pathways may be up- or down-regulated in different cell types in the PFC of BPD. These results provide novel insights into the molecular mechanisms underlying the pathophysiology of BPD. |
| first_indexed | 2024-04-13T23:55:41Z |
| format | Article |
| id | doaj.art-8a84af76fcd54bfe8cc77884b53fdc13 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-04-13T23:55:41Z |
| publishDate | 2022-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-8a84af76fcd54bfe8cc77884b53fdc132022-12-22T02:23:54ZengNature Publishing GroupTranslational Psychiatry2158-31882022-05-0112111110.1038/s41398-022-01944-8Differential expression of gene co-expression networks related to the mTOR signaling pathway in bipolar disorderSung Woo Park0Mi Kyoung Seo1Maree J. Webster2Jung Goo Lee3Sanghyeon Kim4Department of Convergence Biomedical Science, College of Medicine, Inje UniversityPaik Institute for Clinical Research, Inje UniversityStanley Brain Research Laboratory, Stanley Medical Research InstitutePaik Institute for Clinical Research, Inje UniversityStanley Brain Research Laboratory, Stanley Medical Research InstituteAbstract Bipolar disorder (BPD) is a severe mental illness characterized by episodes of depression and mania. To investigate the molecular mechanisms underlying the pathophysiology of bipolar disorder, we performed transcriptome studies using RNA-seq data from the prefrontal cortex (PFC) of individuals with BPD and matched controls, as well as data from cell culture and animal model studies. We found 879 differentially expressed genes that were also replicated in an independent cohort of post-mortem samples. Genes involving the mechanistic target of rapamycine (mTOR) pathway were down-regulated, while genes interrelated with the mTOR pathway such as Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway were up-regulated. Gene co-expression network analyses identified a module related to the mTOR pathway that was up-regulated in BPD and also enriched for markers of endothelial cells. We also found a down-regulated co-expression module enriched for genes involved in mTOR signalling and in mTOR related pathways and enriched with neuronal markers. The mTOR related modules were also replicated in the independent cohort of samples. To investigate whether the expression of the modules related to mTOR signalling pathway could be differentially regulated in different cell types we performed comparative network analyses in experimental models. We found both up-regulated modules in the PFC significantly overlapped with an up-regulated module in the brain endothelial cells from mice treated with lipopolysaccharides (LPS) and mTOR related pathways such as JAK-STAT, PI3K-Akt and ribosome were enriched in the common genes. In addition, the down-regulated module in the PFC significantly overlapped with a down-regulated module from neurons treated with the mTOR inhibitor, Torin1 and mTOR signalling, autophagy, and synaptic vesicle cycles were significantly enriched in the common genes. These results suggest that co-expression networks related to mTOR signalling pathways may be up- or down-regulated in different cell types in the PFC of BPD. These results provide novel insights into the molecular mechanisms underlying the pathophysiology of BPD.https://doi.org/10.1038/s41398-022-01944-8 |
| spellingShingle | Sung Woo Park Mi Kyoung Seo Maree J. Webster Jung Goo Lee Sanghyeon Kim Differential expression of gene co-expression networks related to the mTOR signaling pathway in bipolar disorder Translational Psychiatry |
| title | Differential expression of gene co-expression networks related to the mTOR signaling pathway in bipolar disorder |
| title_full | Differential expression of gene co-expression networks related to the mTOR signaling pathway in bipolar disorder |
| title_fullStr | Differential expression of gene co-expression networks related to the mTOR signaling pathway in bipolar disorder |
| title_full_unstemmed | Differential expression of gene co-expression networks related to the mTOR signaling pathway in bipolar disorder |
| title_short | Differential expression of gene co-expression networks related to the mTOR signaling pathway in bipolar disorder |
| title_sort | differential expression of gene co expression networks related to the mtor signaling pathway in bipolar disorder |
| url | https://doi.org/10.1038/s41398-022-01944-8 |
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