Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy.

[adrenomyeloneuropathy]

X-linked adrenoleukodystrophy (X-ALD ) is an inherited disorder characterized by axonopathy and demyelination in the central nervous system and adrenal insufficiency . Main X-ALD phenotypes are : (i ) an adult adrenomyeloneuropathy (AMN ) with axonopathy in spinal cords , (ii ) cerebral AMN with brain demyelination (cAMN ) and (iii ) a childhood variant , cALD , characterized by severe cerebral demyelination . Loss of function of the ABCD 1 peroxisomal fatty acid transporter and subsequent accumulation of very -long -chain fatty acids (VLCFAs ) are the common culprits to all forms of X-ALD , an aberrant microglial activation accounts for the cerebral forms , whereas inflammation allegedly plays no role in AMN . How VLCFA accumulation leads to neurodegeneration and what factors account for the dissimilar clinical outcomes and prognosis of X-ALD variants remain elusive . To gain insights into these questions , we undertook a transcriptomic approach followed by a functional -enrichment analysis in spinal cords of the animal model of AMN , the Abcd 1 (-) null mice , and in normal-appearing white matter of cAMN and cALD patients . We report that the mouse model shares with cAMN and cALD a common signature comprising dysregulation of oxidative phosphorylation , adipocytokine and insulin signaling pathways , and protein synthesis . Functional validation by quantitative polymerase chain reaction , western blots and assays in spinal cord organotypic cultures confirmed the interplay of these pathways through IkB kinase , being VLCFA in excess a causal , upstream trigger promoting the altered signature . We conclude that X-ALD is , in all its variants , a metabolic /inflammatory syndrome , which may offer new targets in X-ALD therapeutics .

Diseases
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Diseases presenting "cerebral forms" symptom

adrenomyeloneuropathy

x-linked adrenoleukodystrophy

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