{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T23:56:09Z","timestamp":1788998169230,"version":"build-2803163510"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T00:00:00Z","timestamp":1746489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMW","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100021135","name":"TOP","doi-asserted-by":"publisher","award":["91217006"],"award-info":[{"award-number":["91217006"]}],"id":[{"id":"10.13039\/100021135","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Vanishing white matter (VWM) is a leukodystrophy caused by mutations in any of the genes encoding the subunits of the eukaryotic translation initiation factor 2B (eIF2B), a central factor in mRNA translation initiation and regulator of the translation rate during the integrated stress response. Clinically, VWM is characterized by chronic motor and cognitive decline and premature death. Neuropathology shows selective white matter involvement with dysmorphic, immature astrocytes and defective reactive astrogliosis, while oligodendrocytes show increased expression of immaturity and proliferation markers and neurons look normal. Expression of the ATF4 transcriptome is increased in the white matter. These characteristics have been replicated successfully in eIF2B mutant mouse models. Until now, the relative contribution of each cell type to the development of VWM has remained unclear. Understanding the vulnerability of specific cell types for VWM is crucial for understanding disease mechanisms and developing effective therapies.<\/jats:p>\n                  <jats:p>We generated astrocyte-, oligodendrocyte- and neuron-specific Eif2b5 conditional mouse lines to determine the role of each mutant cell type in the onset and development of the disease. We evaluated motor performance, white matter pathology and the expression of myelin-related proteins. We analysed astrocyte and oligodendrocyte density, maturity, morphology, proliferation and apoptosis. We investigated the expression of the integrated stress response-\/ATF4-related genes and proteins, in addition to their localization within the glial cells.<\/jats:p>\n                  <jats:p>At age 9 months, we found that astrocyte-specific Eif2b5 conditional mice showed very mild ataxia, extensive intramyelinic vacuolization, normal density and maturity of oligodendrocytes, and high expression of ATF4-related genes. Oligodendrocyte-specific Eif2b5 conditional mice developed gait ataxia that matched the phenotype of the whole-body Eif2b5 mutant line. Myelin looked normal, but numerous axons were unmyelinated; astrocytes were reactive, and oligodendrocytes were immature and in cell cycle. The enhanced ATF4 transcriptome was minor compared with the astrocyte-specific lines. The neuron-specific Eif2b5 conditional line exhibited a very mild phenotype and none of the major characteristics of VWM.<\/jats:p>\n                  <jats:p>Our findings highlight a complex effect of Eif2b5 mutations in different brain cell types leading to the clinical and neuropathological characteristics of VWM. Oligodendrocytes are the major contributors to the development of ataxia, but astrocyte-specific Eif2b5 conditional mice display several histological and molecular key features of VWM. In conclusion, the view of a single cell population being responsible for the onset and development of VWM needs to be replaced by the concept of VWM as a disease involving diverse cell types.<\/jats:p>","DOI":"10.1093\/brain\/awaf171","type":"journal-article","created":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T08:06:50Z","timestamp":1746259610000},"page":"4112-4126","source":"Crossref","is-referenced-by-count":3,"title":["Cell-specific\n                    <i>Eif2b5<\/i>\n                    mutant mice: novel insights into roles of macroglia in vanishing white matter"],"prefix":"10.1093","volume":"148","author":[{"given":"Javier","family":"Tri\u00f1anes-Ramos","sequence":"first","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children\u2019s Hospital, Amsterdam University Medical Centers , Amsterdam, 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Bugiani","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children\u2019s Hospital, Amsterdam University Medical Centers , Amsterdam, 1105 AZ ,","place":["The Netherlands"]},{"name":"Department of Pathology, Amsterdam University Medical Centers , Amsterdam, 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma M","family":"van Rooijen-van Leeuwen","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children\u2019s Hospital, Amsterdam University Medical Centers , Amsterdam, 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliette A","family":"Chevalier","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children\u2019s Hospital, Amsterdam University Medical Centers , Amsterdam, 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan Jiew","family":"Siu","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children\u2019s Hospital, Amsterdam University Medical Centers , Amsterdam, 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise L H","family":"van Utenhove","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children\u2019s Hospital, Amsterdam University Medical Centers , Amsterdam, 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leoni","family":"Hoogterp","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children\u2019s Hospital, Amsterdam University Medical Centers , Amsterdam, 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diede","family":"Witkamp","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children\u2019s Hospital, Amsterdam University Medical Centers , Amsterdam, 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Oudejans","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children\u2019s Hospital, Amsterdam University Medical Centers , Amsterdam, 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bastiaan","family":"Lodder","sequence":"additional","affiliation":[{"name":"Axonal Signaling Group, Netherlands Institute for Neurosciences, Royal Netherlands Academy for Arts and Sciences , Amsterdam, 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3883-5682","authenticated-orcid":false,"given":"Maarten H P","family":"Kole","sequence":"additional","affiliation":[{"name":"Axonal Signaling Group, Netherlands Institute for Neurosciences, Royal Netherlands Academy for Arts and Sciences , Amsterdam, 1105 AZ ,","place":["The Netherlands"]},{"name":"Department of Biology, Faculty of Science, Cell Biology, Neurobiology and Biophysics, Utrecht University , Utrecht, 3584 CH ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gesine","family":"Saher","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Max Planck Institute of Experimental Medicine , G\u00f6ttingen, 37077 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus-Armin","family":"Nave","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Max Planck Institute of Experimental Medicine , G\u00f6ttingen, 37077 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Truus E M","family":"Abbink","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children\u2019s Hospital, Amsterdam University Medical Centers , Amsterdam, 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8912-0954","authenticated-orcid":false,"given":"Marjo S","family":"van der Knaap","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children\u2019s Hospital, Amsterdam University Medical Centers , Amsterdam, 1105 AZ 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