Cortical Pathology in Vanishing White Matter.

Autor:	Man JHK; Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands.; Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands.; Molecular and Cellular Mechanisms, Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands., van Gelder CAGH; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 3584 CS Utrecht, The Netherlands.; Netherlands Proteomics Center, 3584 CS Utrecht, The Netherlands., Breur M; Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands.; Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands.; Molecular and Cellular Mechanisms, Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands., Okkes D; Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands.; Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands.; Molecular and Cellular Mechanisms, Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands., Molenaar D; Department of Systems Bioinformatics, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands., van der Sluis S; Department of Child and Adolescent Psychology and Psychiatry, Complex Trait Genetics, Amsterdam Neuroscience, VU University Medical Center, 1081 HV Amsterdam, The Netherlands., Abbink T; Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands.; Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands.; Molecular and Cellular Mechanisms, Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands., Altelaar M; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 3584 CS Utrecht, The Netherlands.; Netherlands Proteomics Center, 3584 CS Utrecht, The Netherlands., van der Knaap MS; Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands.; Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands.; Molecular and Cellular Mechanisms, Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands.; Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands., Bugiani M; Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands.; Molecular and Cellular Mechanisms, Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands.; Department of Pathology, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Cells [Cells] 2022 Nov 12; Vol. 11 (22). Date of Electronic Publication: 2022 Nov 12.
DOI:	10.3390/cells11223581
Abstrakt:	Vanishing white matter (VWM) is classified as a leukodystrophy with astrocytes as primary drivers in its pathogenesis. Magnetic resonance imaging has documented the progressive thinning of cortices in long-surviving patients. Routine histopathological analyses, however, have not yet pointed to cortical involvement in VWM. Here, we provide a comprehensive analysis of the VWM cortex. We employed high-resolution-mass-spectrometry-based proteomics and immunohistochemistry to gain insight into possible molecular disease mechanisms in the cortices of VWM patients. The proteome analysis revealed 268 differentially expressed proteins in the VWM cortices compared to the controls. A majority of these proteins formed a major protein interaction network. A subsequent gene ontology analysis identified enrichment for terms such as cellular metabolism, particularly mitochondrial activity. Importantly, some of the proteins with the most prominent changes in expression were found in astrocytes, indicating cortical astrocytic involvement. Indeed, we confirmed that VWM cortical astrocytes exhibit morphological changes and are less complex in structure than control cells. Our findings also suggest that these astrocytes are immature and not reactive. Taken together, we provide insights into cortical involvement in VWM, which has to be taken into account when developing therapeutic strategies.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu Plný text ve formátu PDF