Vanishing White Matter Disease

Elroy‐Stein, Orna; Schiffmann, Raphael

doi:10.1016/b978-0-12-410529-4.00086-3

Cited by 4 publications

(2 citation statements)

References 79 publications

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“…Vanishing white matter (VWM) disease, also termed Childhood ataxia with CNS hypomyelination (CACH), is a genetic autosomal recessive leukodystrophy characterized by progressive loss of white matter in both hemispheres of the brain. The consequent axonal degeneration results in progressive impairments of neurologic functions, leading to complete paralysis and early death ( Schiffmann and Elroy-Stein, 2006 ; Elroy-Stein and Schiffmann, 2015 ). Disease onset and clinical symptoms refer to congenital, classical, and adult forms.…”

Section: Introductionmentioning

confidence: 99%

Drug Screening Identifies Sigma-1-Receptor as a Target for the Therapy of VWM Leukodystrophy

Atzmon

Herrero

Sharet-Eshed

et al. 2018

Front. Mol. Neurosci.

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Vanishing white matter (VWM) disease is an autosomal genetic leukodystrophy caused by mutations in subunits of eukaryotic translation initiation factor 2B (eIF2B). The clinical symptoms exhibit progressive loss of white matter in both hemispheres of the brain, accompanied by motor functions deterioration, neurological deficits, and early death. To date there is no treatment for VWM disease. The aim of this work was to expedite rational development of a therapeutic opportunity. Our approach was to design a computer-aided strategy for an efficient and reliable screening of drug-like molecules; and to use primary cultures of fibroblasts isolated from the Eif2b5R132H/R132H VWM mouse model for screening. The abnormal mitochondria content phenotype of the mutant cells was chosen as a read-out for a simple cell-based fluorescent assay to assess the effect of the tested compounds. We obtained a hit rate of 0.04% (20 hits out of 50,000 compounds from the selected library). All primary hits decreased mitochondria content and brought it closer to WT levels. Structural similarities between our primary hits and other compounds with known targets allowed the identification of three putative cellular pathways/targets: 11β-hydroxysteroid dehydrogenase type 1, Sonic hedgehog (Shh), and Sigma-1-Receptor (S1R). In addition to initial experimental indication of Shh pathway impairment in VWM mouse brains, the current study provides evidence that S1R is a relevant target for pharmaceutical intervention for potential treatment of the disease. Specifically, we found lower expression level of S1R protein in fibroblasts, astrocytes, and whole brains isolated from Eif2b5R132H/R132H compared to WT mice, and confirmed that one of the hits is a direct binder of S1R, acting as agonist. Furthermore, we provide evidence that treatment of mutant mouse fibroblasts and astrocytes with various S1R agonists corrects the functional impairments of their mitochondria and prevents their need to increase their mitochondria content for compensation purposes. Moreover, S1R activation enhances the survival rate of mutant cells under ER stress conditions, bringing it to WT levels. This study marks S1R as a target for drug development toward treatment of VWM disease. Moreover, it further establishes the important connection between white matter well-being and S1R-mediated proper mitochondria/ER function.

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Section: Introductionmentioning

confidence: 99%

Drug Screening Identifies Sigma-1-Receptor as a Target for the Therapy of VWM Leukodystrophy

Atzmon

Herrero

Sharet-Eshed

et al. 2018

Front. Mol. Neurosci.

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“…While mild mutations involve only brain pathology, severe mutations in rare congenital VWM patients involve damage to additional organs (Fogli and Boespflug‐Tanguy ; Bugiani et al . ; Elroy‐Stein and Schiffmann ). Hence, brain white matter formation and maintenance is more sensitive to impairments of translation regulation compared to other tissues.…”

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Mutant eIF2B leads to impaired mitochondrial oxidative phosphorylation in vanishing white matter disease

Raini

Sharet

Herrero

et al. 2017

Journal of Neurochemistry

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Eukaryotic translation initiation factor 2B (eIF2B) is a master regulator of protein synthesis under normal and stress conditions. Mutations in any of the five genes encoding its subunits lead to vanishing white matter (VWM) disease, a recessive genetic deadly illness caused by progressive loss of white matter in the brain. In this study we used fibroblasts, which are not involved in the disease, to demonstrate the involvement of eIF2B in mitochondrial function and abundance. Mass spectrometry of total proteome of mouse embryonic fibroblasts (MEFs) isolated from Eif2b5 mice revealed unbalanced stoichiometry of proteins involved in oxidative phosphorylation and of mitochondrial translation machinery components, among others. Mutant MEFs exhibit 55% decrease in oxygen consumption rate per mtDNA content and 47% increase in mitochondrial abundance (p < 0.005), reflecting adaptation to energy requirements. A more robust eIF2B-associated oxidative respiration deficiency was found in mutant primary astrocytes, which exhibit > 3-fold lower ATP-linked respiration per cell despite a 2-fold increase in mtDNA content (p < 0.03). The 2-fold increase in basal and stimulated glycolysis in mutant astrocytes (p ≤ 0.03), but not in MEFs, demonstrates their higher energetic needs and further explicates their involvement in the disease. The data demonstrate the critical role of eIF2B in tight coordination of expression from nuclear and mitochondrial genomes and illuminates the importance of mitochondrial function in VWM pathology. Further dissection of the signaling network associated with eIF2B function will help generating therapeutic strategies for VWM disease and possibly other neurodegenerative disorders.

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Astrocyte Differentiation of Human Pluripotent Stem Cells: New Tools for Neurological Disorder Research

Chandrasekaran

Avci

Leist

et al. 2016

Front. Cell. Neurosci.

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114

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Astrocytes have a central role in brain development and function, and so have gained increasing attention over the past two decades. Consequently, our knowledge about their origin, differentiation and function has increased significantly, with new research showing that astrocytes cultured alone or co-cultured with neurons have the potential to improve our understanding of various central nervous system diseases, such as amyotrophic lateral sclerosis, Alzheimer’s disease, or Alexander disease. The generation of astrocytes derived from pluripotent stem cells (PSCs) opens up a new area for studying neurologic diseases in vitro; these models could be exploited to identify and validate potential drugs by detecting adverse effects in the early stages of drug development. However, as it is now known that a range of astrocyte populations exist in the brain, it will be important in vitro to develop standardized protocols for the in vitro generation of astrocyte subsets with defined maturity status and phenotypic properties. This will then open new possibilities for co-cultures with neurons and the generation of neural organoids for research purposes. The aim of this review article is to compare and summarize the currently available protocols and their strategies to generate human astrocytes from PSCs. Furthermore, we discuss the potential role of human-induced PSCs derived astrocytes in disease modeling.

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Vanishing White Matter Disease

Cited by 4 publications

References 79 publications

Drug Screening Identifies Sigma-1-Receptor as a Target for the Therapy of VWM Leukodystrophy

Drug Screening Identifies Sigma-1-Receptor as a Target for the Therapy of VWM Leukodystrophy

Mutant eIF2B leads to impaired mitochondrial oxidative phosphorylation in vanishing white matter disease

Astrocyte Differentiation of Human Pluripotent Stem Cells: New Tools for Neurological Disorder Research

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