Aim: 

Peroxisomes are essential organelles degradating fatty acids that accumulate in several diseases. In search for novel roles of fatty acid peroxisomal transport proteins ABCD1 and ABCD2, we screened the metabolome changes in two neuronal tissues induced by genetic ablation of those functionally redundant proteins.

Methods: 

The double knock-out (ABCD1-/- and ABCD2-/-) mice, showing axonal damage followed by myelin degeneration as phenotypical changes, partially reproduces human X-linked adrenoleukodystrophy. Samples (n=6) were obtained from lumbar spinal cord and sciatic nerve both from double knock out and wild type male littermates aged 20 months. All samples were submitted to analyses using an untargeted metabolomic approach, after liquid chromatography time-of-flight mass spectrometry. After isotopic adjustment, differences between samples were analyzed by the ANOVA analysis with the Benjamini and Hochberg false discovery rate statistic for correction of multiple testing.

Results: 

As expected, masses compatible with lipid species (both higly unsaturated triacylglycerides and phosphatydilinositol) were increased in knock-out within spinal cord. In sciatic nerve, decreased concentration of different triacylglycerides and increased of phosphatydic acids suggested tissue-specific changes in lipidome profile. Furthermore, decreased amount of glycolysis intermediates and steroid metabolites suggested complex metabolic dearrangements, together with accumulation of very short, highly unsaturated fatty acids in sciatic nerve. These data correlate with tissue and age-dependent changes in protein oxidative damage, suggesting different penetrances of pathogenic phenotype among different anatomic locations.

Conclusions: 

Asides from expected lipid changes, loss of peroxisomal transporters ABCD1 and ABCD2 leads to tissue specific metabolomic profiles, suggesting peroxisomal-glycolysis metabolic crosstalk.