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Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter.

ABSTRACT: Leukodystrophies are often devastating diseases, presented with progressive clinical signs as spasticity, ataxia and cognitive decline, and lack proper treatment options. New therapy strategies for leukodystrophies mostly focus on oligodendrocyte replacement to rescue lack of myelin in the brain, even though disease pathology also often involves other glial cells and the spinal cord. In this study we investigated spinal cord pathology in a mouse model for Vanishing White Matter disease (VWM) and show that astrocytes in the white matter are severely affected. Astrocyte pathology starts postnatally in the sensory tracts, followed by changes in the astrocytic populations in the motor tracts. Studies in post-mortem tissue of two VWM patients, a 13-year-old boy and a 6-year-old girl, confirmed astrocyte abnormalities in the spinal cord. For proper development of new treatment options for VWM and, possibly, other leukodystrophies, future studies should investigate spinal cord involvement.

SUBMITTER: Leferink PS

PROVIDER: S-EPMC5838785 | biostudies-other | 2018 Apr

REPOSITORIES: biostudies-other

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Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter.

Leferink Prisca S PS Breeuwsma Nicole N Bugiani Marianna M van der Knaap Marjo S MS Heine Vivi M VM

Glia 20171229 4

Leukodystrophies are often devastating diseases, presented with progressive clinical signs as spasticity, ataxia and cognitive decline, and lack proper treatment options. New therapy strategies for leukodystrophies mostly focus on oligodendrocyte replacement to rescue lack of myelin in the brain, even though disease pathology also often involves other glial cells and the spinal cord. In this study we investigated spinal cord pathology in a mouse model for Vanishing White Matter disease (VWM) and ...[more]

PMID: 29285798

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Project description:Vanishing white matter (VWM) is a leukodystrophy with predominantly early-childhood onset. Affected children display various neurological signs, including ataxia and spasticity, and die early. VWM patients have bi-allelic mutations in any of the five genes encoding the subunits of the eukaryotic translation factor 2B (eIF2B). eIF2B regulates protein synthesis rates under basal and cellular stress conditions. The underlying molecular mechanism of how mutations in eIF2B result in VWM is unknown. Previous studies suggest that brain white matter astrocytes are primarily affected in VWM. We hypothesized that the translation rate of certain astrocytic mRNAs is affected by the mutations, resulting in astrocytic dysfunction. Here we subjected primary astrocyte cultures of wild type (wt) and VWM (2b5ho ) mice to pulsed labeling proteomics based on stable isotope labeling with amino acids in cell culture (SILAC) with an L-azidohomoalanine (AHA) pulse to select newly synthesized proteins. AHA was incorporated into newly synthesized proteins in wt and 2b5ho astrocytes with similar efficiency, without affecting cell viability. We quantified proteins synthesized in astrocytes of wt and 2b5ho mice. This proteomic profiling identified a total of 80 proteins that were regulated by the eIF2B mutation. We confirmed increased expression of PROS1 in 2b5ho astrocytes and brain. A DAVID enrichment analysis showed that approximately 50% of the eIF2B-regulated proteins used the secretory pathway. A small-scale metabolic screen further highlighted a significant change in the metabolite 6-phospho-gluconate, indicative of an altered flux through the pentose phosphate pathway (PPP). Some of the proteins migrating through the secretory pathway undergo oxidative folding reactions in the endoplasmic reticulum (ER), which produces reactive oxygen species (ROS). The PPP produces NADPH to remove ROS. The proteomic and metabolomics data together suggest a deregulation of ER function in 2b5ho mouse astrocytes.

Project description:Vanishing white matter (VWM) is a leukodystrophy caused by biallelic pathogenic variants in eukaryotic translation initiation factor 2B. Neuropathology includes lack of reactive gliosis, paucity of myelin, and axonal abnormalities. Alteration in proteins involved in cellular metabolism has also been implicated in the disease. It, however, remains unclear which factors contribute to VWM pathogenesis. Here, we aimed at gaining insight into the basis of VWM pathogenesis using the 2b5ho mouse model of VWM. We first investigated the temporal proteome in the cerebellum, corpus callosum, cortex, and brainstem of 2b5ho and wild type (WT) mice. Protein changes observed in 2b5ho mice were then cross-referenced with published proteomic datasets from post mortem VWM patient brain tissue to define alterations relevant to the human disease. By comparing 2b5ho mice with their region- and age-matched WT counterparts, we identified region-specific protein changes associated with disease development and progression. We showed that the proteome in the cerebellum and cortex of 2b5ho mice was already deregulated prior to pathology development, whereas proteome changes in the corpus callosum only occurred after onset of pathology. Remarkably, protein changes in the brainstem were transient, indicating that a compensatory mechanism might occur in this region throughout the disease course. Gene ontology overrepresentation analysis revealed that proteome changes observed in 2b5ho mouse brains reflect alterations in features well-known in VWM. Side-by-side comparison of the 2b5ho mouse and VWM patient brain proteomes revealed that part of protein changes were the same as in VWM patients. These could represent relevant changes that contribute to the disease or even drive its progression in VWM patients. Taken together, we show that the proteome in the brain of 2b5ho mice is affected in a region-specific and time-dependent manner. We found that the 2b5ho mouse model partly replicates the human disease at the protein level, and provides a spatiotemporal proteome resource to study aspects of VWM pathogenesis. This resource highlights alterations presenting from early to late disease stages, and those that possibly drive disease progression.

Dataset Information

Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter.

Publications

Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter.

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