Pathomechanisms underlying X-adrenoleukodystrophy: a three-hit hypothesis.
X-adrenoleukodystrophy (X-ALD) is a complex disease where inactivation of ABCD1 gene results in clinically diverse phenotypes, the fatal disorder of cerebral ALD (cALD) or a milder disorder of adrenomyeloneuropathy (AMN). Loss of ABCD1 function results in defective beta oxidation of very long chain fatty acids (VLCFA) resulting in excessive accumulation of VLCFA, the biochemical "hall mark" of X-ALD. At present, the ABCD1-mediated mechanisms that determine the different phenotype of X-ALD are not well understood. The studies reviewed here suggest for a "three-hit hypothesis" for neuropathology of cALD. An improved understanding of the molecular mechanisms associated with these three phases of cALD disease should facilitate the development of effective pharmacological therapeutics for X-ALD.
Singh
Inderjit
I
Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, SC, USA.
Pujol
Aurora
A
D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000326:Adrenoleukodystrophy / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001921:Brain / Q000473:pathology*; D005227:Fatty Acids / Q000235:genetics; D006801:Humans; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics
C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D005227:Fatty Acids