Decreased Resolvin D1 and Increased Fatty Acid Oxidation Contribute to Severity Score of Krabbe Disease in Twitcher Mice

Abstract

Background: Krabbe disease is due to a deficiency of lysosomal enzyme galactosylceramidase, which leads to destruction of the myelin sheath around nerves in the brain and spinal cord. In addition, Krabbe disease is associated with neuroinflammation in which harmful amounts of lipids are produced. To assess the importance of the regulation of lipid metabolism in the pathogenesis and intervention options in Krabbe disease, the aim of this study was to identify a set of specific biomarkers in a mouse model of the disease and to analyze the correlation between each biomarker. Methods: In this study, fatty acid mediators were investigated in twitcher mice, a natural model of Krabbe disease, and the genotype was determined. Mass spectrometry was used to quantify F₂-isoprostanes and immune techniques were used to investigate F₂-isoprostanes, resolvin D1 (RvD1), peroxisome proliferator-activated receptor gamma, apelin, and the apelin receptor in the brains of heterozygous and affected homozygous mice and in wild-type control mice. Results: The results of molecular analysis showed that there was a reduction in peroxisome proliferator-activated receptor gamma in the brains of both heterozygous and affected homozygous mice (p < 0.001). In addition, in the brains of mice with Krabbe disease RvD1 levels were decreased (p < 0.001), oxidation of arachidonic acid was increased (p < 0.001) and low levels of apelin (p < 0.001) were associated with an increase in apelin receptor (p < 0.05). RvD1 and apelin levels were associated with disease severity (r = –0.638, p < 0.001 and r = –0.725, p < 0.001, respectively). Conclusion: Our results indicate that mutation of the galactosylceramidase gene is associated with altered homeostasis of fatty acid oxidative metabolism. These homeostatic alterations reflect the disease phenotype. Our findings highlight a relevant aspect of fatty acid metabolism in the Krabbe disease brain and support the view that fatty acid metabolism is an active player in the pathogenesis of this still incurable disease.