Astrocytes are central in the pathomechanisms of vanishing white matter

Stephanie Dooves; Marianna Bugiani; Nienke L Postma; Emiel Polder; Niels Land; Stephen T Horan; Anne-Lieke F van Deijk; Aleid van de Kreeke; Gerbren Jacobs; Caroline Vuong; J. Klooster; M. Kamermans; Joke Wortel; Maarten Loos; Lisanne E Wisse; Gert C Scheper; Truus E M Abbink; Vivi M Heine; Marjo S van der Knaap

doi:10.1172/JCI83908

Astrocytes are central in the pathomechanisms of vanishing white matter

Stephanie Dooves, Marianna Bugiani, Nienke L Postma, Emiel Polder, Niels Land, Stephen T Horan, Anne-Lieke F van Deijk, Aleid van de Kreeke, Gerbren Jacobs, Caroline Vuong, J. Klooster, M. Kamermans, Joke Wortel, Maarten Loos, Lisanne E Wisse, Gert C Scheper, Truus E M Abbink, Vivi M Heine, Marjo S van der Knaap

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Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

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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.

Originele taal-2	Engels
Pagina's (van-tot)	1512-24
Aantal pagina's	13
Tijdschrift	Journal of Clinical Investigation
Volume	126
Nummer van het tijdschrift	4
DOI's	https://doi.org/10.1172/JCI83908
Status	Gepubliceerd - 01 apr. 2016

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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., 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, 126(4), 1512-24. https://doi.org/10.1172/JCI83908

@article{15538bf7eb0b498d9d53ad657af6e194,

title = "Astrocytes are central in the pathomechanisms of vanishing white matter",

abstract = "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 M{\"u}ller 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.",

author = "Stephanie Dooves and Marianna Bugiani and Postma, {Nienke L} and Emiel Polder and Niels Land and Horan, {Stephen T} and {van Deijk}, {Anne-Lieke F} and {van de Kreeke}, Aleid and Gerbren Jacobs and Caroline Vuong and J. Klooster and M. Kamermans and Joke Wortel and Maarten Loos and Wisse, {Lisanne E} and Scheper, {Gert C} and Abbink, {Truus E M} and Heine, {Vivi M} and {van der Knaap}, {Marjo S}",

year = "2016",

month = apr,

day = "1",

doi = "10.1172/JCI83908",

language = "English",

volume = "126",

pages = "1512--24",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "4",

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Dooves, S, Bugiani, M, Postma, NL, Polder, E, Land, N, Horan, ST, van Deijk, A-LF, van de Kreeke, A, Jacobs, G, Vuong, C, Klooster, J, Kamermans, M, Wortel, J, Loos, M, Wisse, LE, Scheper, GC, Abbink, TEM, Heine, VM & van der Knaap, MS 2016, 'Astrocytes are central in the pathomechanisms of vanishing white matter', Journal of Clinical Investigation, vol. 126, nr. 4, blz. 1512-24. https://doi.org/10.1172/JCI83908

TY - JOUR

T1 - Astrocytes are central in the pathomechanisms of vanishing white matter

AU - Dooves, Stephanie

AU - Bugiani, Marianna

AU - Postma, Nienke L

AU - Polder, Emiel

AU - Land, Niels

AU - Horan, Stephen T

AU - van Deijk, Anne-Lieke F

AU - van de Kreeke, Aleid

AU - Jacobs, Gerbren

AU - Vuong, Caroline

AU - Klooster, J.

AU - Kamermans, M.

AU - Wortel, Joke

AU - Loos, Maarten

AU - Wisse, Lisanne E

AU - Scheper, Gert C

AU - Abbink, Truus E M

AU - Heine, Vivi M

AU - van der Knaap, Marjo S

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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.

AB - 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.

U2 - 10.1172/JCI83908

DO - 10.1172/JCI83908

M3 - Article

C2 - 26974157

SN - 0021-9738

VL - 126

SP - 1512

EP - 1524

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 4

ER -

Astrocytes are central in the pathomechanisms of vanishing white matter

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