TY - JOUR
T1 - Cortical Pathology in Vanishing White Matter
AU - Man, Jodie H.K.
AU - van Gelder, Charlotte A.G.H.
AU - Breur, Marjolein
AU - Okkes, Daniel
AU - Molenaar, Douwe
AU - van der Sluis, Sophie
AU - Abbink, Truus
AU - Altelaar, Maarten
AU - van der Knaap, Marjo S.
AU - Bugiani, Marianna
N1 - Special Issue: Astrocytes in CNS Disorders. Funding Information: The research was funded by the ZonMw TOP grant 91217006. S.v.d.S is supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). M.B. (Marianna Bugiani) is supported by the ZonMW VENI Grant 016.196.107. Publisher Copyright: © 2022 by the authors.
PY - 2022/11/2
Y1 - 2022/11/2
N2 - 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.
AB - 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.
KW - astrocytes
KW - astrocytopathy
KW - cortex
KW - leukodystrophy
KW - proteomics
KW - vanishing white matter
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U2 - https://doi.org/10.3390/cells11223581
DO - https://doi.org/10.3390/cells11223581
M3 - Article
C2 - 36429009
SN - 2073-4409
VL - 11
SP - 1
EP - 19
JO - Cells
JF - Cells
IS - 22
M1 - 3581
ER -