Department of Child Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
Charlotte A. G. H. van Gelder
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 3584 CS Utrecht, The Netherlands
Marjolein Breur
Department of Child Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
Daniel Okkes
Department of Child Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
Douwe Molenaar
Department of Systems Bioinformatics, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
Sophie van der Sluis
Department of Child and Adolescent Psychology and Psychiatry, Complex Trait Genetics, Amsterdam Neuroscience, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
Truus Abbink
Department of Child Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
Maarten Altelaar
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 3584 CS Utrecht, The Netherlands
Marjo S. van der Knaap
Department of Child Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
Marianna Bugiani
Amsterdam Leukodystrophy Center, Emma Children’s Hospital, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands
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.
