Proteomic dissection of vanishing white matter pathogenesis.

Autor: Man JHK; Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Molecular and Cellular Mechanisms, Amsterdam Neuroscience, Amsterdam, The Netherlands., Zarekiani P; Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Mosen P; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, The Netherlands.; Netherlands Proteomics Center, Utrecht, The Netherlands., de Kok M; Department of Molecular Cell Biology and Immunology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Debets DO; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, The Netherlands.; Netherlands Proteomics Center, Utrecht, The Netherlands., Breur M; Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Molecular and Cellular Mechanisms, Amsterdam Neuroscience, Amsterdam, The Netherlands., Altelaar M; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, The Netherlands.; Netherlands Proteomics Center, Utrecht, The Netherlands., van der Knaap MS; Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Molecular and Cellular Mechanisms, Amsterdam Neuroscience, Amsterdam, The Netherlands.; Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Bugiani M; Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. m.bugiani@amsterdamumc.nl.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2024 May 24; Vol. 81 (1), pp. 234. Date of Electronic Publication: 2024 May 24.
DOI: 10.1007/s00018-024-05258-4
Abstrakt: Vanishing white matter (VWM) is a leukodystrophy caused by biallelic pathogenic variants in eukaryotic translation initiation factor 2B. To date, it remains unclear which factors contribute to VWM pathogenesis. Here, we investigated the basis of VWM pathogenesis using the 2b5 ho mouse model. We first mapped the temporal proteome in the cerebellum, corpus callosum, cortex, and brainstem of 2b5 ho and wild-type (WT) mice. Protein changes observed in 2b5 ho mice were then cross-referenced with published proteomic datasets from VWM patient brain tissue to define alterations relevant to the human disease. By comparing 2b5 ho mice with their region- and age-matched WT counterparts, we showed that the proteome in the cerebellum and cortex of 2b5 ho mice was already dysregulated prior to pathology development, whereas proteome changes in the corpus callosum only occurred after pathology onset. Remarkably, protein changes in the brainstem were transient, indicating that a compensatory mechanism might occur in this region. Importantly, 2b5 ho mouse brain proteome changes reflect features well-known in VWM. Comparison of the 2b5 ho mouse and VWM patient brain proteomes revealed shared changes. These could represent changes that contribute to the disease or even drive its progression in patients. Taken together, we show that the 2b5 ho mouse brain proteome is affected in a region- and time-dependent manner. We found that the 2b5 ho mouse model partly replicates the human disease at the protein level, providing a resource to study aspects of VWM pathogenesis by highlighting alterations from early to late disease stages, and those that possibly drive disease progression.
(© 2024. The Author(s).)
Databáze: MEDLINE
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