Astrocytes are central in the pathomechanisms of vanishing white matter

Dooves, Stephanie; Bugiani, Marianna; Postma, Nienke L.; Polder, Emiel; Land, Niels; Horan, Stephen T.; Deijk, Anne-Lieke F van; Kreeke, Aleid van de; 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.; Knaap, Marjo S. van der

doi:10.1172/jci83908

Cited by 127 publications

(268 citation statements)

References 59 publications

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“…Our data reveals that astrocytes are most prominently affected in the WM of the VWM spinal cord, which is in line with earlier studies showing that astrocytes are central in the brain pathophysiology of VWM (Bugiani et al, 2011; Dooves, Bugiani, et al, 2016). We report that pathology starts in the dorsal and lateral WM tracts, with most severe defects in the sensory tracts, followed later by the vestibulospinal motor tracts.…”

Section: Discussionsupporting

confidence: 93%

“…In this study we investigated glial pathology in post‐mortem spinal cord tissue of a VWM mouse model and 2 VWM patients. We showed that the glial cells in the spinal cord of a representative mouse model for VWM (Dooves, Bugiani, et al, 2016) are severely affected. The cellular density in the WM is increased, dysmorphic, nestin‐expressing astrocytes are abundantly present, OPCs are increased in density, and lesions are present throughout the WM.…”

Section: Discussionmentioning

confidence: 87%

“…The VWM mice were homozygous for a mutation in the Eif2b5 gene ( Eif2b5 Arg191His/Arg191His ), on a C57Bl/6J background strain (referred to as 2b5 ho ; Dooves, Bugiani, et al, 2016). Heterozygous littermates, referred to as 2b5 he , were used as controls.…”

Section: Methodsmentioning

confidence: 99%

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Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter

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Breeuwsma

Bugiani

et al. 2017

Glia

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Leukodystrophies are often devastating diseases, presented with progressive clinical signs as spasticity, ataxia and cognitive decline, and lack proper treatment options. New therapy strategies for leukodystrophies mostly focus on oligodendrocyte replacement to rescue lack of myelin in the brain, even though disease pathology also often involves other glial cells and the spinal cord. In this study we investigated spinal cord pathology in a mouse model for Vanishing White Matter disease (VWM) and show that astrocytes in the white matter are severely affected. Astrocyte pathology starts postnatally in the sensory tracts, followed by changes in the astrocytic populations in the motor tracts. Studies in post‐mortem tissue of two VWM patients, a 13‐year‐old boy and a 6‐year‐old girl, confirmed astrocyte abnormalities in the spinal cord. For proper development of new treatment options for VWM and, possibly, other leukodystrophies, future studies should investigate spinal cord involvement.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 87%

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Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter

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Breeuwsma

Bugiani

et al. 2017

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“…Mouse models (background strain C57Bl/6J) were generated by inserting a point mutation in Eif2b4 ( Eif2b4Arg484Trp/Arg484Trp ) or Eif2b5 ( Eif2b5Arg191His/Arg191His ) and bred into homozygous single mutants as well as heterozygous‐homozygous double‐mutants, which in increasing order of severity are referred to as, respectively, 2b4 ho , 2b5 ho , and 2b4/2b5 heho mice 23. These mice replicate the human disease in clinical and pathological features and in variation in severity.…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies indicate that astrocyte dysfunction is primary and oligodendrocyte dysfunction secondary 16, 23. As astrocytes and oligodendrocytes are important for axonal support, their dysfunction in VWM may affect axonal integrity and function, but a primary axonal defect in VWM has not been ruled out 24, 25, 26.…”

Section: Introductionmentioning

confidence: 99%

Axonal abnormalities in vanishing white matter

Klok

Bugiani

Vries

et al. 2018

Ann Clin Transl Neurol

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ObjectiveWe aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter.MethodsAxons and myelin were analyzed using electron microscopy and immunohistochemistry on Eif2b4 and Eif2b5 single‐ and double‐mutant mice and patient brain tissue. In addition, astrocyte‐forebrain co‐culture studies were performed.ResultsIn the corpus callosum of Eif2b5‐mutant mice, myelin sheath thickness, axonal diameter, and G‐ratio developed normally up to 4 months. At 7 months, however, axons had become thinner, while in control mice axonal diameters had increased further. Myelin sheath thickness remained close to normal, resulting in an abnormally low G‐ratio in Eif2b5‐mutant mice. In more severely affected Eif2b4‐Eif2b5 double‐mutants, similar abnormalities were already present at 4 months, while in milder affected Eif2b4 mutants, few abnormalities were observed at 7 months. Additionally, from 2 months onward an increased percentage of thin, unmyelinated axons and increased axonal density were present in Eif2b5‐mutant mice. Co‐cultures showed that Eif2b5 mutant astrocytes induced increased axonal density, also in control forebrain tissue, and that control astrocytes induced normal axonal density, also in mutant forebrain tissue. In vanishing white matter patient brains, axons and myelin sheaths were thinner than normal in moderately and severely affected white matter. In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities were minimal.InterpretationIn vanishing white matter, axons are initially normal and atrophy later. Astrocytes are central in this process. If therapy becomes available, axonal pathology may be prevented with early intervention.

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Vanishing white matter: deregulated integrated stress response as therapy target

Abbink

Wisse

Jaku

et al. 2019

Ann Clin Transl Neurol

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Objective Vanishing white matter (VWM) is a fatal, stress‐sensitive leukodystrophy that mainly affects children and is currently without treatment. VWM is caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B) that is crucial for initiation of mRNA translation and its regulation during the integrated stress response (ISR). Mutations reduce eIF2B activity. VWM pathomechanisms remain unclear. In contrast with the housekeeping function of eIF2B, astrocytes are selectively affected in VWM. One study objective was to test our hypothesis that in the brain translation of specific mRNAs is altered by eIF2B mutations, impacting primarily astrocytes. The second objective was to investigate whether modulation of eIF2B activity could ameliorate this altered translation and improve the disease. Methods Mice with biallelic missense mutations in eIF2B that recapitulate human VWM were used to screen for mRNAs with altered translation in brain using polysomal profiling. Findings were verified in brain tissue from VWM patients using qPCR and immunohistochemistry. The compound ISRIB (for “ISR inhibitor”) was administered to VWM mice to increase eIF2B activity. Its effect on translation, neuropathology, and clinical signs was assessed. Results In brains of VWM compared to wild‐type mice we observed the most prominent changes in translation concerning ISR mRNAs; their expression levels correlated with disease severity. We substantiated these findings in VWM patients’ brains. ISRIB normalized expression of mRNA markers, ameliorated brain white matter pathology and improved motor skills in VWM mice. Interpretation The present findings show that ISR deregulation is central in VWM pathomechanisms and a viable target for therapy.

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Astrocytes are central in the pathomechanisms of vanishing white matter

Cited by 127 publications

References 59 publications

Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter

Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter

Axonal abnormalities in vanishing white matter

Vanishing white matter: deregulated integrated stress response as therapy target

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