Astrocytes are central in the pathomechanisms of vanishing white matter
| Autor: | Dooves, Stephanie, Bugiani, Marianna, Postma, Nienke L., Polder, Emiel, Land, Niels, Horan, Stephen T., van Deijk, Anne-Lieke F., van de Kreeke, Aleid, Jacobs, Gerbren, Vuong, Caroline, Klooster, Jan, Kamermans, Maarten, Wortel, Joke, Loos, Maarten, Wisse, Lisanne E., Scheper, Gert C., Abbink, Truus E. M., Heine, Vivi M., van der Knaap, Marjo S. |
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| Přispěvatelé: | Complex Trait Genetics, Molecular and Cellular Neurobiology, Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Netherlands Institute for Neuroscience (NIN), Graduate School, Paediatric Pulmonology, ANS - Cellular & Molecular Mechanisms, Human Genetics, ANS - Amsterdam Neuroscience, Pediatric surgery, Pathology, Ophthalmology, Internal medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell type Pathology medicine.medical_specialty Cells medicine.disease_cause Astrocytes/metabolism White matter 03 medical and health sciences Mice 0302 clinical medicine Leukoencephalopathies medicine White Matter/metabolism Animals Humans Cells Cultured Mutation Cultured Leukoencephalopathies/genetics biology Animal Leukodystrophy General Medicine Eukaryotic Initiation Factor-2B/genetics medicine.disease Phenotype White Matter Oligodendrocyte Mice Mutant Strains Coculture Techniques Cell biology Mutant Strains Disease Models Animal Eukaryotic Initiation Factor-2B Oligodendroglia 030104 developmental biology medicine.anatomical_structure Oligodendroglia/metabolism Cell culture Astrocytes eIF2B Disease Models biology.protein 030217 neurology & neurosurgery Research Article |
| Zdroj: | Journal of Clinical Investigation, 1512-1524. The American Society for Clinical Investigation ISSUE=126;STARTPAGE=1512;ENDPAGE=1524;ISSN=0021-9738;TITLE=Journal of Clinical Investigation Journal of Clinical Investigation, 126(4), 1512-24. The American Society for Clinical Investigation Journal of clinical investigation, 126(4), 1512-1524. The American Society for Clinical Investigation Dooves, S, Bugiani, M, Postma, N L, Polder, E, Land, N, Horan, S T, van Deijk, A L F, van de Kreeke, A, Jacobs, J G, Vuong, C, Klooster, J, Kamermans, M, Wortel, J, Loos, M, Wisse, L E, Scheper, G C, Abbink, G E M, Heine, V M & Knaap, M 2016, ' Astrocytes are central in the pathomechanisms of vanishing white matter ', Journal of Clinical Investigation, no. 126, 4, pp. 1512-1524 . https://doi.org/10.1172/JCI83908 Dooves, S, Bugiani, M, Postma, N L, Polder, E, Land, N, Horan, S T, van Deijk, A-L F, van de Kreeke, A, Jacobs, G, Jacobs, G, Vuong, C, Klooster, J, Kamermans, M, Wortel, J, Loos, M, Wisse, L E, Scheper, G C, Abbink, T E M, Heine, V M & van der Knaap, M S 2016, ' Astrocytes are central in the pathomechanisms of vanishing white matter ', Journal of Clinical Investigation, vol. 126, no. 4, pp. 1512-1524 . https://doi.org/10.1172/JCI83908 Journal of Clinical Investigation, 126(4), 1512-1524. The American Society for Clinical Investigation |
| ISSN: | 0021-9738 |
| Popis: | Vanishing white matter (VWM) is a fatal leukodystrophy that is caused by mutations in genes encoding subunits of eukaryotic translation initiation factor 2B (eIF2B). Disease onset and severity are codetermined by genotype. White matter astrocytes and oligodendrocytes are almost exclusively affected; however, the mechanisms of VWM development remain unclear. Here, we used VWM mouse models, patients' tissue, and cell cultures to investigate whether astrocytes or oligodendrocytes are the primary affected cell type. We generated 2 mouse models with mutations (Eif2b5Arg191His/Arg191His and Eif2b4Arg484Trp/Arg484Trp) that cause severe VWM in humans and then crossed these strains to develop mice with various mutation combinations. Phenotypic severity was highly variable and dependent on genotype, reproducing the clinical spectrum of human VWM. In all mutant strains, impaired maturation of white matter astrocytes preceded onset and paralleled disease severity and progression. Bergmann glia and retinal Müller cells, nonforebrain astrocytes that have not been associated with VWM, were also affected, and involvement of these cells was confirmed in VWM patients. In coculture, VWM astrocytes secreted factors that inhibited oligodendrocyte maturation, whereas WT astrocytes allowed normal maturation of VWM oligodendrocytes. These studies demonstrate that astrocytes are central in VWM pathomechanisms and constitute potential therapeutic targets. Importantly, astrocytes should also be considered in the pathophysiology of other white matter disorders. |
| Databáze: | OpenAIRE |
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