Vanishing white matter: deregulated integrated stress response as therapy target
Abstract 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 regu...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2019-08-01
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| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.50826 |
| _version_ | 1818573683416891392 |
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| author | Truus E. M. Abbink Lisanne E. Wisse Ermelinda Jaku Michiel J. Thiecke Daniel Voltolini‐González Hein Fritsen Sander Bobeldijk Timo J. terBraak Emiel Polder Nienke L. Postma Marianna Bugiani Eduard A. Struijs Mark Verheijen Nina Straat Sophie van derSluis Adri A. M. Thomas Douwe Molenaar Marjo S. van derKnaap |
| author_facet | Truus E. M. Abbink Lisanne E. Wisse Ermelinda Jaku Michiel J. Thiecke Daniel Voltolini‐González Hein Fritsen Sander Bobeldijk Timo J. terBraak Emiel Polder Nienke L. Postma Marianna Bugiani Eduard A. Struijs Mark Verheijen Nina Straat Sophie van derSluis Adri A. M. Thomas Douwe Molenaar Marjo S. van derKnaap |
| author_sort | Truus E. M. Abbink |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-15T00:14:54Z |
| format | Article |
| id | doaj.art-bc70e13747d84b12b5b25ba59f4dcbfe |
| institution | Directory Open Access Journal |
| issn | 2328-9503 |
| language | English |
| last_indexed | 2024-12-15T00:14:54Z |
| publishDate | 2019-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj.art-bc70e13747d84b12b5b25ba59f4dcbfe2022-12-21T22:42:29ZengWileyAnnals of Clinical and Translational Neurology2328-95032019-08-01681407142210.1002/acn3.50826Vanishing white matter: deregulated integrated stress response as therapy targetTruus E. M. Abbink0Lisanne E. Wisse1Ermelinda Jaku2Michiel J. Thiecke3Daniel Voltolini‐González4Hein Fritsen5Sander Bobeldijk6Timo J. terBraak7Emiel Polder8Nienke L. Postma9Marianna Bugiani10Eduard A. Struijs11Mark Verheijen12Nina Straat13Sophie van derSluis14Adri A. M. Thomas15Douwe Molenaar16Marjo S. van derKnaap17Child Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsChild Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsChild Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsChild Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsChild Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsChild Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsChild Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsChild Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsChild Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsChild Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsChild Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsMetabolic Unit, Department of Clinical Chemistry Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsDepartment of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsChild Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsComplex Trait Genetics, Department of Clinical Genetics, Center for Neurogenomics and Cognitive Research Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsDevelopmental Biology Utrecht University Utrecht The NetherlandsSystems Bioinformatics Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsChild Neurology Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience Amsterdam The NetherlandsAbstract 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.https://doi.org/10.1002/acn3.50826 |
| spellingShingle | Truus E. M. Abbink Lisanne E. Wisse Ermelinda Jaku Michiel J. Thiecke Daniel Voltolini‐González Hein Fritsen Sander Bobeldijk Timo J. terBraak Emiel Polder Nienke L. Postma Marianna Bugiani Eduard A. Struijs Mark Verheijen Nina Straat Sophie van derSluis Adri A. M. Thomas Douwe Molenaar Marjo S. van derKnaap Vanishing white matter: deregulated integrated stress response as therapy target Annals of Clinical and Translational Neurology |
| title | Vanishing white matter: deregulated integrated stress response as therapy target |
| title_full | Vanishing white matter: deregulated integrated stress response as therapy target |
| title_fullStr | Vanishing white matter: deregulated integrated stress response as therapy target |
| title_full_unstemmed | Vanishing white matter: deregulated integrated stress response as therapy target |
| title_short | Vanishing white matter: deregulated integrated stress response as therapy target |
| title_sort | vanishing white matter deregulated integrated stress response as therapy target |
| url | https://doi.org/10.1002/acn3.50826 |
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