Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis
Abstract Inter-individual differences in cortisol production by the hypothalamus–pituitary–adrenal (HPA) axis are thought to contribute to clinical and pathological heterogeneity of multiple sclerosis (MS). At the same time, accumulating evidence indicates that MS pathogenesis may originate in the n...
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| Format: | Article |
| Language: | English |
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BMC
2019-04-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-019-0705-7 |
| _version_ | 1818388854848094208 |
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| author | Jeroen Melief Marie Orre Koen Bossers Corbert G. van Eden Karianne G. Schuurman Matthew R. J. Mason Joost Verhaagen Jörg Hamann Inge Huitinga |
| author_facet | Jeroen Melief Marie Orre Koen Bossers Corbert G. van Eden Karianne G. Schuurman Matthew R. J. Mason Joost Verhaagen Jörg Hamann Inge Huitinga |
| author_sort | Jeroen Melief |
| collection | DOAJ |
| description | Abstract Inter-individual differences in cortisol production by the hypothalamus–pituitary–adrenal (HPA) axis are thought to contribute to clinical and pathological heterogeneity of multiple sclerosis (MS). At the same time, accumulating evidence indicates that MS pathogenesis may originate in the normal-appearing white matter (NAWM). Therefore, we performed a genome-wide transcriptional analysis, by Agilent microarray, of post-mortem NAWM of 9 control subjects and 18 MS patients to investigate to what extent gene expression reflects disease heterogeneity and HPA-axis activity. Activity of the HPA axis was determined by cortisol levels in cerebrospinal fluid and by numbers of corticotropin-releasing neurons in the hypothalamus, while duration of MS and time to EDSS6 served as indicator of disease severity. Applying weighted gene co-expression network analysis led to the identification of a range of gene modules with highly similar co-expression patterns that strongly correlated with various indicators of HPA-axis activity and/or severity of MS. Interestingly, molecular profiles associated with relatively mild MS and high HPA-axis activity were characterized by increased expression of genes that actively regulate inflammation and by molecules involved in myelination, anti-oxidative mechanism, and neuroprotection. Additionally, group-wise comparisons of gene expression in white matter from control subjects and NAWM from (subpopulations of) MS patients uncovered disease-associated gene expression as well as strongly up- or downregulated genes in patients with relatively benign MS and/or high HPA-axis activity, with many differentially expressed genes being previously undescribed in the context of MS. Overall, the data suggest that HPA-axis activity strongly impacts on molecular mechanisms in NAWM of MS patients, but partly also independently of disease severity. |
| first_indexed | 2024-12-14T04:32:28Z |
| format | Article |
| id | doaj.art-91ae7c2831ea493c9b3564de0c282815 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-14T04:32:28Z |
| publishDate | 2019-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-91ae7c2831ea493c9b3564de0c2828152022-12-21T23:17:03ZengBMCActa Neuropathologica Communications2051-59602019-04-017111910.1186/s40478-019-0705-7Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosisJeroen Melief0Marie Orre1Koen Bossers2Corbert G. van Eden3Karianne G. Schuurman4Matthew R. J. Mason5Joost Verhaagen6Jörg Hamann7Inge Huitinga8Department of Neuroimmunology, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and SciencesDepartment of Astrocyte Biology and Neurodegeneration, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and SciencesDepartment of Neuroregeneration, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and SciencesDepartment of Neuroimmunology, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and SciencesDepartment of Neuroimmunology, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and SciencesDepartment of Neuroimmunology, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and SciencesDepartment of Neuroregeneration, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and SciencesDepartment of Neuroimmunology, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and SciencesDepartment of Neuroimmunology, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and SciencesAbstract Inter-individual differences in cortisol production by the hypothalamus–pituitary–adrenal (HPA) axis are thought to contribute to clinical and pathological heterogeneity of multiple sclerosis (MS). At the same time, accumulating evidence indicates that MS pathogenesis may originate in the normal-appearing white matter (NAWM). Therefore, we performed a genome-wide transcriptional analysis, by Agilent microarray, of post-mortem NAWM of 9 control subjects and 18 MS patients to investigate to what extent gene expression reflects disease heterogeneity and HPA-axis activity. Activity of the HPA axis was determined by cortisol levels in cerebrospinal fluid and by numbers of corticotropin-releasing neurons in the hypothalamus, while duration of MS and time to EDSS6 served as indicator of disease severity. Applying weighted gene co-expression network analysis led to the identification of a range of gene modules with highly similar co-expression patterns that strongly correlated with various indicators of HPA-axis activity and/or severity of MS. Interestingly, molecular profiles associated with relatively mild MS and high HPA-axis activity were characterized by increased expression of genes that actively regulate inflammation and by molecules involved in myelination, anti-oxidative mechanism, and neuroprotection. Additionally, group-wise comparisons of gene expression in white matter from control subjects and NAWM from (subpopulations of) MS patients uncovered disease-associated gene expression as well as strongly up- or downregulated genes in patients with relatively benign MS and/or high HPA-axis activity, with many differentially expressed genes being previously undescribed in the context of MS. Overall, the data suggest that HPA-axis activity strongly impacts on molecular mechanisms in NAWM of MS patients, but partly also independently of disease severity.http://link.springer.com/article/10.1186/s40478-019-0705-7Multiple sclerosisNormal-appearing white matterHPA axisTranscriptome |
| spellingShingle | Jeroen Melief Marie Orre Koen Bossers Corbert G. van Eden Karianne G. Schuurman Matthew R. J. Mason Joost Verhaagen Jörg Hamann Inge Huitinga Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis Acta Neuropathologica Communications Multiple sclerosis Normal-appearing white matter HPA axis Transcriptome |
| title | Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis |
| title_full | Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis |
| title_fullStr | Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis |
| title_full_unstemmed | Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis |
| title_short | Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis |
| title_sort | transcriptome analysis of normal appearing white matter reveals cortisol and disease associated gene expression profiles in multiple sclerosis |
| topic | Multiple sclerosis Normal-appearing white matter HPA axis Transcriptome |
| url | http://link.springer.com/article/10.1186/s40478-019-0705-7 |
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