Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy

• DOI: 10.1093/hmg/ddr536
• Publication Date: 2011-11-18T01:44:01Z
• Authors: Agatha Schlüter; Lluís Espinosa; Stéphane Fourcade; Jorge Galino; Eva López; Ekaterina Ilieva; Laia Morató; Muriel Asheuer; Ted Cook; Alistair McLaren; Juliet Reid; Fiona Kelly; Stewart Bates; Patrick Aubourg; Elena Galea; Aurora Pujol
• Keywords: Adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder characterized by axonopathy and demyelination in the central nervous system adrenal insufficiency. Main X-ALD phenotypes are: (i) adult adrenomyeloneuropathy (AMN) with spinal cords, (ii) cerebral AMN brain (cAMN) (iii) a childhood variant, cALD, severe demyelination. Loss of function ABCD1 peroxisomal fatty acid transporter subsequent accumulation very-long-chain acids (VLCFAs) are common culprits to all forms X-ALD, aberrant microglial activation accounts for forms, whereas inflammation allegedly plays no role AMN. How VLCFA leads neurodegeneration what factors account dissimilar clinical outcomes prognosis variants remain elusive. To gain insights into these questions, we undertook transcriptomic approach followed functional-enrichment analysis cords animal model AMN, Abcd1− null mice, normal-appearing white matter cAMN cALD patients. We report that mouse shares signature comprising dysregulation oxidative phosphorylation, adipocytokine insulin signaling pathways, protein synthesis. Functional validation quantitative polymerase chain reaction, western blots assays cord organotypic cultures confirmed interplay pathways through IkB kinase, being excess causal, upstream trigger promoting altered signature. conclude is, its variants, metabolic/inflammatory syndrome, which may offer new targets therapeutics.