Cortical Pathology in Vanishing White Matter

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.

Automated summary

This study comprehensively analyzed the cortex of vanishing white matter (VWM) patients using high-resolution mass spectrometry-based proteomics and immunohistochemistry. The findings revealed a large number of differentially expressed proteins in the VWM cortex, forming a major protein interaction network. Gene ontology analysis further indicated enrichment for cellular metabolism, particularly mitochondrial activity. Importantly, the study identified astrocytic involvement in the cortical pathology of VWM, with morphological changes and decreased complexity observed in VWM cortical astrocytes compared to control cells. These astrocytes were found to be immature and non-reactive. These insights into cortical involvement in VWM have significant implications for the development of therapeutic strategies.