Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature
In a substantial share of patients suffering from multiple sclerosis (MS), neurological functions slowly deteriorate despite a lack of radiological activity. Such a silent progression, observed in either relapsing-remitting or progressive forms of MS, is driven by mechanisms that appear to be indepe...
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/14993 |
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| author | Serge Nataf Marine Guillen Laurent Pays |
| author_facet | Serge Nataf Marine Guillen Laurent Pays |
| author_sort | Serge Nataf |
| collection | DOAJ |
| description | In a substantial share of patients suffering from multiple sclerosis (MS), neurological functions slowly deteriorate despite a lack of radiological activity. Such a silent progression, observed in either relapsing-remitting or progressive forms of MS, is driven by mechanisms that appear to be independent from plaque activity. In this context, we previously reported that, in the spinal cord of MS patients, periplaques cover large surfaces of partial demyelination characterized notably by a transforming growth factor beta (TGF-beta) molecular signature and a decreased expression of the oligodendrocyte gene <i>NDRG1</i> (N-Myc downstream regulated 1). In the present work, we re-assessed a previously published RNA expression dataset in which brain periplaques were originally used as internal controls. When comparing the mRNA profiles obtained from brain periplaques with those derived from control normal white matter samples, we found that, irrespective of plaque activity, brain periplaques exhibited a TGF-beta molecular signature, an increased expression of <i>TGFB2</i> (transforming growth factor beta 2) and a decreased expression of the oligodendrocyte genes <i>NDRG1</i> (N-Myc downstream regulated 1) and <i>MAG</i> (myelin-associated glycoprotein). From these data obtained at the mRNA level, a survey of the human proteome allowed predicting a protein–protein interaction network linking TGFB2 to the down-regulation of both <i>NDRG1</i> and <i>MAG</i> in brain periplaques. To further elucidate the role of NDRG1 in periplaque-associated partial demyelination, we then extracted the interaction network linking NDRG1 to proteins detected in human central myelin sheaths. We observed that such a network was highly significantly enriched in RNA-binding proteins that notably included several HNRNPs (heterogeneous nuclear ribonucleoproteins) involved in the post-transcriptional regulation of <i>MAG</i>. We conclude that both brain and spinal cord periplaques host a chronic process of tissue remodeling, during which oligodendrocyte myelinating functions are altered. Our findings further suggest that TGFB2 may fuel such a process. Overall, the present work provides additional evidence that periplaque-associated partial demyelination may drive the silent progression observed in a subset of MS patients. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:46:02Z |
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| spelling | doaj.art-f4e070cceb3e4838b7544b5410a20fc32023-11-24T11:11:23ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231499310.3390/ijms232314993Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta SignatureSerge Nataf0Marine Guillen1Laurent Pays2Bank of Tissues and Cells, Hospices Civils de Lyon, Hôpital Edouard Herriot, Place d’Arsonval, F-69003 Lyon, FranceBank of Tissues and Cells, Hospices Civils de Lyon, Hôpital Edouard Herriot, Place d’Arsonval, F-69003 Lyon, FranceBank of Tissues and Cells, Hospices Civils de Lyon, Hôpital Edouard Herriot, Place d’Arsonval, F-69003 Lyon, FranceIn a substantial share of patients suffering from multiple sclerosis (MS), neurological functions slowly deteriorate despite a lack of radiological activity. Such a silent progression, observed in either relapsing-remitting or progressive forms of MS, is driven by mechanisms that appear to be independent from plaque activity. In this context, we previously reported that, in the spinal cord of MS patients, periplaques cover large surfaces of partial demyelination characterized notably by a transforming growth factor beta (TGF-beta) molecular signature and a decreased expression of the oligodendrocyte gene <i>NDRG1</i> (N-Myc downstream regulated 1). In the present work, we re-assessed a previously published RNA expression dataset in which brain periplaques were originally used as internal controls. When comparing the mRNA profiles obtained from brain periplaques with those derived from control normal white matter samples, we found that, irrespective of plaque activity, brain periplaques exhibited a TGF-beta molecular signature, an increased expression of <i>TGFB2</i> (transforming growth factor beta 2) and a decreased expression of the oligodendrocyte genes <i>NDRG1</i> (N-Myc downstream regulated 1) and <i>MAG</i> (myelin-associated glycoprotein). From these data obtained at the mRNA level, a survey of the human proteome allowed predicting a protein–protein interaction network linking TGFB2 to the down-regulation of both <i>NDRG1</i> and <i>MAG</i> in brain periplaques. To further elucidate the role of NDRG1 in periplaque-associated partial demyelination, we then extracted the interaction network linking NDRG1 to proteins detected in human central myelin sheaths. We observed that such a network was highly significantly enriched in RNA-binding proteins that notably included several HNRNPs (heterogeneous nuclear ribonucleoproteins) involved in the post-transcriptional regulation of <i>MAG</i>. We conclude that both brain and spinal cord periplaques host a chronic process of tissue remodeling, during which oligodendrocyte myelinating functions are altered. Our findings further suggest that TGFB2 may fuel such a process. Overall, the present work provides additional evidence that periplaque-associated partial demyelination may drive the silent progression observed in a subset of MS patients.https://www.mdpi.com/1422-0067/23/23/14993multiple sclerosisperiplaquesmyelin maintenancedemyelinationTGF-betaMAG |
| spellingShingle | Serge Nataf Marine Guillen Laurent Pays Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature International Journal of Molecular Sciences multiple sclerosis periplaques myelin maintenance demyelination TGF-beta MAG |
| title | Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature |
| title_full | Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature |
| title_fullStr | Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature |
| title_full_unstemmed | Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature |
| title_short | Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature |
| title_sort | irrespective of plaque activity multiple sclerosis brain periplaques exhibit alterations of myelin genes and a tgf beta signature |
| topic | multiple sclerosis periplaques myelin maintenance demyelination TGF-beta MAG |
| url | https://www.mdpi.com/1422-0067/23/23/14993 |
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