Abstract
BackgroundLeukodystrophies are devastating diseases characterized by dys- and hypo-myelination. While there are a number of histological and imaging studies of these disorders, there are limited biochemical data available. We undertook targeted lipidomic analyses of Pelizaeus-Merzbacher disease (PMD) fibroblasts, PMD lymphocytes, and 158JP oligodendrocytes, a murine model of PMD, to define the lipid changes in these cell models. Further targeted metabolomics analyses were conducted to obtain a preliminary evaluation of the metabolic consequences of lipid changes and gene mutations in these cell models.ResultsIn both PMD fibroblasts and lymphocytes, and 158JP oligodendrocytes, ethanolamine plasmalogens were significantly decreased. Labeling studies with 158JP oligodendrocytes further demonstrated a decreased rate of lipid remodeling at sn-2. Targeted metabolomics analyses of these cells revealed dramatic increases in cellular levels of myo-inositol. Further uptake studies demonstrated increased rates of myo-inositol uptake by PMD lymphocytes.ConclusionsOur data demonstrating PlsEtn decrements, support previous studies indicating leukodystrophy cells possess significant peroxisomal deficits. Our data for the first time also demonstrate that decrements in peroxisomal function coupled with the PLP1 gene defects of PMD, result in changes in the function of membrane myo-inositol solute carriers resulting in dramatic increases in cellular myo-inositol levels.
Highlights
Leukodystrophies are devastating diseases characterized by dys- and hypo-myelination
The leukodystrophies include a heterogeneous group of both childhood and late onset genetic diseases that primarily result in dys- or hypo-myelination [1,2]
Fibroblast cells and oligodendrocytes were harvested when plates reached confluence using a cocktail of Versene and TryPLe express (2:1; Gibco)
Summary
Leukodystrophies are devastating diseases characterized by dys- and hypo-myelination. We undertook targeted lipidomic analyses of Pelizaeus-Merzbacher disease (PMD) fibroblasts, PMD lymphocytes, and 158JP oligodendrocytes, a murine model of PMD, to define the lipid changes in these cell models. Further targeted metabolomics analyses were conducted to obtain a preliminary evaluation of the metabolic consequences of lipid changes and gene mutations in these cell models. The leukodystrophies include a heterogeneous group of both childhood and late onset genetic diseases that primarily result in dys- or hypo-myelination [1,2]. These disorders are highly misdiagnosed such that disease incidence is much greater than previously thought [3]. We undertook a targeted lipidomics analysis of the established
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