Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis
| العنوان: | Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis |
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| المؤلفون: | Vincent Tse, Yuichiro Itoh, Rhonda R. Voskuhl, Ellis Jang, Alessia Tassoni, Macy Akiyo Matsukawa, Emily Ren, Timothy Takazo Suen, Noriko Itoh |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, MS animal models, Gene Expression, oligodendrocytes, Biology, Transcriptome, Cuprizone, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Estrogen Receptor beta, Homeostasis, Humans, Remyelination, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Microglia, Sequence Analysis, RNA, Multiple sclerosis, Neurodegeneration, Experimental autoimmune encephalomyelitis, cholesterol, Middle Aged, Biological Sciences, medicine.disease, Oligodendrocyte, 3. Good health, Cell biology, Mice, Inbred C57BL, Oligodendroglia, remyelination, medicine.anatomical_structure, PNAS Plus, Case-Control Studies, Female, 030217 neurology & neurosurgery, Neuroscience, Astrocyte |
| الوصف: | Significance Cell-specific and region-specific gene expression can identify therapeutic targets in different neuroanatomic regions during neurodegenerative diseases. Multiple sclerosis (MS) is multifocal, and neuroprotective treatments are needed. Here, RNA sequencing of MS brain suggested study of the transcriptome of oligodendrocyte lineage cells (OLCs) in a location where remyelination occurs in an MS model. Cholesterol-synthesis pathways dominated as top upregulated pathways in OLCs of corpus callosum during remyelination in the cuprizone model. Estrogen receptor-β ligand treatment further increased cholesterol-synthesis pathways through direct effects on OLCs. As fetal OLCs are exposed in utero to high levels of estrogens in maternal blood, we hypothesize that remyelinating properties of estrogen treatment in adults during injury may recapitulate normal developmental myelination by targeting cholesterol homeostasis. Regional differences in neurons, astrocytes, oligodendrocytes, and microglia exist in the brain during health, and regional differences in the transcriptome may occur for each cell type during neurodegeneration. Multiple sclerosis (MS) is multifocal, and regional differences in the astrocyte transcriptome occur in experimental autoimmune encephalomyelitis (EAE), an MS model. MS and EAE are characterized by inflammation, demyelination, and axonal damage, with minimal remyelination. Here, RNA-sequencing analysis of MS tissues from six brain regions suggested a focus on oligodendrocyte lineage cells (OLCs) in corpus callosum. Olig1-RiboTag mice were used to determine the translatome of OLCs in vivo in corpus callosum during the remyelination phase of a chronic cuprizone model with axonal damage. Cholesterol-synthesis gene pathways dominated as the top up-regulated pathways in OLCs during remyelination. In EAE, remyelination was induced with estrogen receptor-β (ERβ) ligand treatment, and up-regulation of cholesterol-synthesis gene expression was again observed in OLCs. ERβ-ligand treatment in the cuprizone model further increased cholesterol synthesis gene expression and enhanced remyelination. Conditional KOs of ERβ in OLCs demonstrated that increased cholesterol-synthesis gene expression in OLCs was mediated by direct effects in both models. To address this direct effect, ChIP assays showed binding of ERβ to the putative estrogen-response element of a key cholesterol-synthesis gene (Fdps). As fetal OLCs are exposed in utero to high levels of estrogens in maternal blood, we discuss how remyelinating properties of estrogen treatment in adults during injury may recapitulate normal developmental myelination through targeting cholesterol homeostasis in OLCs. |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3ca5355ba977623503106b73c32f39f3 https://doi.org/10.1073/pnas.1821306116 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....3ca5355ba977623503106b73c32f39f3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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