Regional vulnerability of brain white matter in vanishing white matter

Vanishing white matter (VWM) is a leukodystrophy that primarily manifests in young children. In this disease, the brain white matter is differentially affected in a predictable pattern with telencephalic brain areas being most severely affected, while others remain allegedly completely spared. Using high-resolution mass spectrometry-based proteomics, we investigated the proteome patterns of the white matter in the severely affected frontal lobe and normal appearing pons in VWM and control cases to identify molecular bases underlying regional vulnerability. By comparing VWM patients to controls, we identified disease-specific proteome patterns. We showed substantial changes in both the VWM frontal and pons white matter at the protein level. Side-by-side comparison of brain region-specific proteome patterns further revealed regional differences. We found that different cell types were affected in the VWM frontal white matter than in the pons. Gene ontology and pathway analyses identified involvement of region specific biological processes, of which pathways involved in cellular respiratory metabolism were overarching features. In the VWM frontal white matter, proteins involved in glycolysis/gluconeogenesis and metabolism of various amino acids were decreased compared to controls. By contrast, in the VWM pons white matter, we found a decrease in proteins involved in oxidative phosphorylation. Taken together, our data show that brain regions are affected in parallel in VWM, but to different degrees. We found region-specific involvement of different cell types and discovered that cellular respiratory metabolism is likely to be differentially affected across white matter regions in VWM. These region-specific changes help explain regional vulnerability to pathology in VWM

Region-specific and age-related differences in astrocytes in the human brain

Astrocyte heterogeneity and its relation to aging in the normal human brain remain poorly understood. We here analyzed astrocytes in gray and white matter brain tissues obtained from donors ranging in age between the neonatal period to over 100 years. We show that astrocytes are differently distributed with higher density in the white matter. This regional difference in cellular density becomes less prominent with age. Additionally, we confirm the presence of morphologically distinct astrocytes, with gray matter astrocytes being morphologically more complex. Notably, gray matter astrocytes morphologically change with age, while white matter astrocytes remain relatively consistent in morphology. Using regional mass spectrometry-based proteomics, we did, however, identify astrocyte specific proteins with regional differences in abundance, reflecting variation in cellular density or expression level. Importantly, the expression of some astrocyte specific proteins region-dependently decreases with age. Taken together, we provide insights into region- and age-related differences in astrocytes in the human brain

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

Heterogeneity of white matter astrocytes in the human brain

Astrocytes regulate central nervous system development, maintain its homeostasis and orchestrate repair upon injury. Emerging evidence support functional specialization of astroglia, both between and within brain regions. Different subtypes of gray matter astrocytes have been identified, yet molecular and functional diversity of white matter astrocytes remains largely unexplored. Nonetheless, their important and diverse roles in maintaining white matter integrity and function are well recognized. Compelling evidence indicate that impairment of normal astrocytic function and their response to injury contribute to a wide variety of diseases, including white matter disorders. In this review, we highlight our current understanding of astrocyte heterogeneity in the white matter of the mammalian brain and how an interplay between developmental origins and local environmental cues contribute to astroglial diversification. In addition, we discuss whether, and if so, how, heterogeneous astrocytes could contribute to white matter function in health and disease and focus on the sparse human research data available. We highlight four leukodystrophies primarily due to astrocytic dysfunction, the so-called astrocytopathies. Insight into the role of astroglial heterogeneity in both healthy and diseased white matter may provide new avenues for therapies aimed at promoting repair and restoring normal white matter function

Regional vulnerability of brain white matter in vanishing white matter

Abstract Vanishing white matter (VWM) is a leukodystrophy that primarily manifests in young children. In this disease, the brain white matter is differentially affected in a predictable pattern with telencephalic brain areas being most severely affected, while others remain allegedly completely spared. Using high-resolution mass spectrometry-based proteomics, we investigated the proteome patterns of the white matter in the severely affected frontal lobe and normal appearing pons in VWM and control cases to identify molecular bases underlying regional vulnerability. By comparing VWM patients to controls, we identified disease-specific proteome patterns. We showed substantial changes in both the VWM frontal and pons white matter at the protein level. Side-by-side comparison of brain region-specific proteome patterns further revealed regional differences. We found that different cell types were affected in the VWM frontal white matter than in the pons. Gene ontology and pathway analyses identified involvement of region specific biological processes, of which pathways involved in cellular respiratory metabolism were overarching features. In the VWM frontal white matter, proteins involved in glycolysis/gluconeogenesis and metabolism of various amino acids were decreased compared to controls. By contrast, in the VWM pons white matter, we found a decrease in proteins involved in oxidative phosphorylation. Taken together, our data show that brain regions are affected in parallel in VWM, but to different degrees. We found region-specific involvement of different cell types and discovered that cellular respiratory metabolism is likely to be differentially affected across white matter regions in VWM. These region-specific changes help explain regional vulnerability to pathology in VWM

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