Vanishing white matter: deregulated integrated stress response as therapy target

Abbink, Truus E.M.; Wisse, Lisanne E.; Jaku, Ermelinda; Thiecke, Michiel J.; Voltolini-González, Daniel; Fritsen, Hein; Bobeldijk, Sander; Braak, Timo J. ter; Polder, Emiel; Postma, Nienke L.; Bugiani, Marianna; Struijs, Eduard A.; Verheijen, Mark H. G.; Straat, Nina; Sluis, Sophie van der; Thomas, Adri A. M.; Molenaar, Douwe; Knaap, Marjo S. van der

doi:10.1002/acn3.50826

Cited by 81 publications

(166 citation statements)

References 44 publications

(67 reference statements)

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“…VWMD astrocytes exhibited increased GADD34 (Fig. 1E), consistent with glia in animal model studies (15) and the hypophosphorylation of eIF2 observed in white matter patient tissue (22).…”

Section: Vwmd Patient Broblasts and Astrocytes Exhibit Dysregulated Isupporting

confidence: 77%

Identification of repurposable cytoprotective drugs in Vanishing White Matter Disease patient-derived cells

Cabral-da-Silva

Maksour

et al. 2020

Preprint

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Background Vanishing white matter disease (VWMD) is a rare leukodystrophy caused by mutations of the guanine exchange factor eIF2B that typically presents with juvenile onset. There are few treatments and no cures for the disease. Recent progress in the field has established mitochondrial dysfunction and endoplasmic reticulum (ER) stress to be strongly implicated in observed glial cell pathology. Drug repurposing offers a rapid approach toward translation of therapeutics with already-licensed drugs. Objective The aim of this study was to use fibroblasts and induced pluripotent stem cell (iPSC)-derived astrocytes from patients bearing the EIF2B5R113H/A403V or EIF2B2G200V/E213G VWMD mutations to identify potentially repurposable FDA-approved drugs based on in vitro assays. Methods Cell viability in the presence or absence of stress was assessed by resazurin reduction activity assay, mitochondrial membrane potential by TMRE fluorescence, and oxidative stress by H2DCFDA oxidation. Relative eIF2B phosphorylation, GADD34 and CHOP were quantified by fluorescent western blot. Results Dysregulated GADD34 and CHOP were identified in patient fibroblasts and iPSC-derived astrocytes under induced stress conditions. A drug screen from a 2,400 FDA-approved drug library with EIF2B5R113H/A403V VWMD patient fibroblasts identified 113 anti-inflammatory drugs as a major class of hits with cytoprotective effects. A panel of potential candidate drugs, including berberine, deflazacort, ursodiol, zileuton, guanabenz and Anavex 2–73, and preclinical ISRIB, increased cell survival of EIF2B5R113H/A403V or EIF2B2G200V/E213G VWMD astrocytes, and were further investigated for their effect on the integrated stress response and mitochondrial stress. Ursodiol demonstrated capacity to ameliorate oxidative stress and loss of mitochondrial membrane potential in VWMD patient iPSC-derived astrocytes in the presence or absence of stress conditions. Conclusion Patient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo.

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“…VWMD astrocytes exhibited increased GADD34 (Fig. 1E), consistent with glia in animal model studies (15) and the hypophosphorylation of eIF2 observed in white matter patient tissue (22).…”

Section: Vwmd Patient Broblasts and Astrocytes Exhibit Dysregulated Isupporting

confidence: 77%

Identification of repurposable cytoprotective drugs in Vanishing White Matter Disease patient-derived cells

Cabral-da-Silva

Maksour

et al. 2020

Preprint

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“…MG132-stressed VWMD astrocytes also showed reduced upregulation of eIF2α phosphorylation and increased CHOP, compared to controls (Figure 1D-F). VWMD astrocytes exhibited increased GADD34 ( Figure 1E), consistent with glia in animal model studies (15) and the hypophosphorylation of eIF2 observed in white matter patient tissue (22).…”

Section: Vwmd Patient Broblasts and Astrocytes Exhibit Dysregulated Isupporting

confidence: 75%

“…ISRIB is thought to allow eIF2B to escape inhibitory complex formation with p-eIF2α, thus limiting repression of protein synthesis while under ER stress (15,24). Treatment of EIF2B5 VWMD mice with ISRIB, or a derivative, 2BAct, ameliorated myelin loss, and improved ISR signature and motor function (15,22,24). It is also worth noting that the stabilising effect of ISRIB may be dependent on the precise mutations and the cellular concentration of p-eIF2α, whereby it has been found to inhibit low level but not high level ISR activation (22,39).…”

Section: Discussionmentioning

confidence: 99%

Identification of Repurposable Cytoprotective Drugs in Vanishing White Matter Disease Patient-Derived cells

Cabral-da-Silva

Maksour

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundVanishing white matter disease (VWMD) is a rare leukodystrophy caused by mutations of the guanine exchange factor eIF2B that typically presents with juvenile onset. There are few treatments and no cures for the disease. Recent progress in the field has established mitochondrial dysfunction and endoplasmic reticulum (ER) stress to be strongly implicated in observed glial cell pathology. Drug repurposing offers a rapid approach toward translation of therapeutics with already-licensed drugs. ObjectiveThe aim of this study was to use fibroblasts and induced pluripotent stem cell (iPSC)-derived astrocytes from patients bearing the EIF2B5R113H/A403V or EIF2B2G200V/E213G VWMD mutations to identify potentially repurposable FDA-approved drugs based on in vitro assays. MethodsCell viability in the presence or absence of stress was assessed by resazurin reduction activity assay, mitochondrial membrane potential by TMRE fluorescence, and oxidative stress by H2DCFDA oxidation. Relative eIF2B phosphorylation, GADD34 and CHOP were quantified by fluorescent western blot. ResultsDysregulated GADD34 and CHOP were identified in patient fibroblasts and iPSC-derived astrocytes under induced stress conditions. A drug screen from a 2,400 FDA-approved drug library with EIF2B5R113H/A403V VWMD patient fibroblasts identified 113 anti-inflammatory drugs as a major class of hits with cytoprotective effects. A panel of potential candidate drugs, including berberine, deflazacort, ursodiol, zileuton, guanabenz and Anavex 2-73, and preclinical ISRIB, increased cell survival of EIF2B5R113H/A403V or EIF2B2G200V/E213G VWMD astrocytes, and were further investigated for their effect on the integrated stress response and mitochondrial stress. Ursodiol demonstrated capacity to ameliorate oxidative stress and loss of mitochondrial membrane potential in VWMD patient iPSC-derived astrocytes in the presence or absence of stress conditions. ConclusionPatient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo.

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“…However, in some circumstances its heightened activity is associated with unfavourable outcomes, motivating a search for ISR inhibitors. When applied to cells or administered to animals, the druglike small molecule, ISRIB, disrupts the ISR (Sidrauski et al, 2013), and has been reported to exert beneficial effects in models of neurodegeneration (Halliday et al, 2015;Zhu et al, 2019), head injury (Chou et al, 2017) and dysmyelination (Wong et al, 2018;Abbink et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

ISRIB blunts the integrated stress response by allosterically antagonising the inhibitory effect of phosphorylated eIF2 on eIF2B

Zyryanova

Kashiwagi

Rato

et al. 2020

Preprint

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The small molecule ISRIB antagonises the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor (GEF) for eIF2. We have found that ISRIB-mediated acceleration of eIF2B activity in vitro is observed preferentially in the presence of eIF2(αP) and is attenuated by mutations that desensitise eIF2B to the inhibitory effects of eIF2(αP). ISRIB’s efficacy as an ISR inhibitor in cells also depends on presence of eIF2(αP). Cryo-EM showed that engagement of both eIF2B regulatory sites by two eIF2(αP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2α during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(αP) and ISRIB reciprocally opposed each other’s binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR.

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Vanishing white matter: deregulated integrated stress response as therapy target

Cited by 81 publications

References 44 publications

Identification of repurposable cytoprotective drugs in Vanishing White Matter Disease patient-derived cells

Identification of repurposable cytoprotective drugs in Vanishing White Matter Disease patient-derived cells

Identification of Repurposable Cytoprotective Drugs in Vanishing White Matter Disease Patient-Derived cells

ISRIB blunts the integrated stress response by allosterically antagonising the inhibitory effect of phosphorylated eIF2 on eIF2B

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