AHCODA-DB

Experiment name: Astrocytes are central in the pathomechanisms of vanishing white matter. (Dooves 2016)
LSID: http://syli.cz/urn:lsid:public.sylics.com:experiment:E257-G33B-5GA4

TreatmentAmountAdministration routeAdministration time
08wk
16wk
20wk


Treatment info:
J Clin Invest. 2016 Apr 1;126(4):1512-24. doi: 10.1172/JCI83908. Epub 2016 Mar 14.

Astrocytes are central in the pathomechanisms of vanishing white matter.

Dooves S, Bugiani M, Postma NL, Polder E, Land N, Horan ST, van Deijk AL, van de Kreeke A, Jacobs G, Vuong C, Klooster J, Kamermans M, Wortel J, Loos M, Wisse LE, Scheper GC, Abbink TE, Heine VM, van der Knaap MS.

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 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.

Mouse info:
Mouse ID Strain Coat color Genotype Ear tag Internal ID Sex Date of Birth Sub experiment 1 Sub experiment 2 Sub experiment 3
PH05303 Eif2b5 black hom R 3912 male 30-07-2012 08wk
PH05304 Eif2b5 black WT RL 3914 male 30-07-2012 08wk
PH05305 Eif2b5 black hom - 3915 male 30-07-2012 08wk
PH05306 Eif2b5 black WT R 3916 male 30-07-2012 08wk
PH05307 Eif2b5 black hom RL 3918 male 30-07-2012 08wk
PH05308 Eif2b5 black WT - 3919 male 30-07-2012 08wk
PH05309 Eif2b5 black hom L 3921 male 30-07-2012 08wk
PH05310 Eif2b5 black hom - 3923 male 30-07-2012 08wk
PH05311 Eif2b5 black WT RL 3926 male 30-07-2012 08wk
PH05312 Eif2b5 black WT R 3936 male 01-08-2012 08wk
PH05313 Eif2b5 black hom L 3937 male 01-08-2012 08wk
PH05314 Eif2b5 black WT RL 3938 male 01-08-2012 08wk
PH05315 Eif2b5 black WT - 3939 male 01-08-2012 08wk
PH05316 Eif2b5 black hom R 3940 male 01-08-2012 08wk
PH05317 Eif2b5 black WT - 4381 male 06-08-2012 08wk
PH05318 Eif2b5 black hom RL 4384 male 06-08-2012 08wk
PH05319 Eif2b5 black hom R 4388 male 06-08-2012 08wk
PH05320 Eif2b5 black WT RL 4390 male 06-08-2012 08wk
PH05321 Eif2b5 black WT RR 4391 male 06-08-2012 08wk
PH05322 Eif2b5 black hom LL 4392 male 06-08-2012 08wk
PH05680 Eif2b5 black hom R 3912 male 30-07-2012 16wk
PH05681 Eif2b5 black WT RL 3914 male 30-07-2012 16wk
PH05682 Eif2b5 black hom - 3915 male 30-07-2012 16wk
PH05683 Eif2b5 black WT R 3916 male 30-07-2012 16wk
PH05684 Eif2b5 black hom RL 3918 male 30-07-2012 16wk
PH05685 Eif2b5 black WT - 3919 male 30-07-2012 16wk
PH05686 Eif2b5 black hom L 3921 male 30-07-2012 16wk
PH05687 Eif2b5 black hom - 3923 male 30-07-2012 16wk
PH05688 Eif2b5 black WT R 3936 male 01-08-2012 16wk
PH05689 Eif2b5 black hom L 3937 male 01-08-2012 16wk
PH05690 Eif2b5 black WT RL 3938 male 01-08-2012 16wk
PH05691 Eif2b5 black WT - 3939 male 01-08-2012 16wk
PH05692 Eif2b5 black hom R 3940 male 01-08-2012 16wk
PH05693 Eif2b5 black WT - 4381 male 06-08-2012 16wk
PH05694 Eif2b5 black hom RL 4384 male 06-08-2012 16wk
PH05739 Eif2b5 black hom R 3912 male 30-07-2012
PH05740 Eif2b5 black WT RL 3914 male 30-07-2012
PH05741 Eif2b5 black hom - 3915 male 30-07-2012
PH05742 Eif2b5 black WT R 3916 male 30-07-2012
PH05743 Eif2b5 black hom RL 3918 male 30-07-2012
PH05744 Eif2b5 black WT - 3919 male 30-07-2012
PH05745 Eif2b5 black hom L 3921 male 30-07-2012
PH05746 Eif2b5 black hom - 3923 male 30-07-2012
PH05747 Eif2b5 black WT R 3936 male 01-08-2012
PH05748 Eif2b5 black hom L 3937 male 01-08-2012
PH05749 Eif2b5 black WT RL 3938 male 01-08-2012
PH05750 Eif2b5 black WT - 3939 male 01-08-2012
PH05751 Eif2b5 black hom R 3940 male 01-08-2012
PH05752 Eif2b5 black WT - 4381 male 06-08-2012
PH05753 Eif2b5 black hom RL 4384 male 06-08-2012
PH05784 Eif2b5 black hom R 3912 male 30-07-2012 20wk
PH05785 Eif2b5 black WT RL 3914 male 30-07-2012 20wk
PH05786 Eif2b5 black hom - 3915 male 30-07-2012 20wk
PH05787 Eif2b5 black WT R 3916 male 30-07-2012 20wk
PH05788 Eif2b5 black hom RL 3918 male 30-07-2012 20wk
PH05789 Eif2b5 black WT - 3919 male 30-07-2012 20wk
PH05790 Eif2b5 black hom L 3921 male 30-07-2012 20wk
PH05791 Eif2b5 black hom - 3923 male 30-07-2012 20wk
PH05792 Eif2b5 black WT R 3936 male 01-08-2012 20wk
PH05793 Eif2b5 black hom L 3937 male 01-08-2012 20wk
PH05794 Eif2b5 black WT RL 3938 male 01-08-2012 20wk
PH05795 Eif2b5 black WT - 3939 male 01-08-2012 20wk
PH05796 Eif2b5 black hom R 3940 male 01-08-2012 20wk
PH05797 Eif2b5 black WT - 4381 male 06-08-2012 20wk
PH05798 Eif2b5 black hom RL 4384 male 06-08-2012 20wk