Abstract
X-linked adrenoleukodystrophy (X-ALD) is a fatal, axonal demyelinating, neurometabolic disease. It results from the functional loss of a member of the peroxisomal ATP-binding cassette transporter subfamily D (ABCD1), which is involved in the metabolism of very long-chain fatty acids (VLCFA). Oxidative damage of proteins caused by excess of the hexacosanoic acid, the most prevalent VLCFA accumulating in X-ALD, is an early event in the neurodegenerative cascade. We demonstrate here that valproic acid (VPA), a widely used anti-epileptic drug with histone deacetylase inhibitor properties, induced the expression of the functionally overlapping ABCD2 peroxisomal transporter. VPA corrected the oxidative damage and decreased the levels of monounsaturated VLCFA (C26:1 n-9), but not saturated VLCFA. Overexpression of ABCD2 alone prevented oxidative lesions to proteins in a mouse model of X-ALD. A 6-month pilot trial of VPA in X-ALD patients resulted in reversion of the oxidative damage of proteins in peripheral blood mononuclear cells. Thus, we propose VPA as a promising novel therapeutic approach that warrants further clinical investigation in X-ALD.
Publication types
-
Clinical Trial
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter, Subfamily D
-
ATP-Binding Cassette Transporters / genetics
-
ATP-Binding Cassette Transporters / metabolism
-
Acetyltransferases / genetics
-
Acetyltransferases / metabolism
-
Adolescent
-
Adrenoleukodystrophy / drug therapy*
-
Adrenoleukodystrophy / enzymology
-
Adrenoleukodystrophy / pathology
-
Animals
-
Antioxidants / pharmacology
-
Antioxidants / therapeutic use*
-
Biomarkers / metabolism
-
Child
-
Fatty Acid Elongases
-
Fatty Acids / metabolism
-
Fibroblasts / drug effects
-
Fibroblasts / metabolism
-
Gene Expression Regulation / drug effects
-
Histone Deacetylase Inhibitors / pharmacology
-
Humans
-
Leukocytes, Mononuclear / drug effects
-
Leukocytes, Mononuclear / metabolism
-
Mice
-
Oxidative Stress / drug effects
-
Rats
-
Rats, Wistar
-
Reactive Oxygen Species / metabolism
-
Spinal Cord / drug effects
-
Spinal Cord / pathology
-
Valproic Acid / pharmacology
-
Valproic Acid / therapeutic use*
Substances
-
ABCD2 protein, mouse
-
ATP Binding Cassette Transporter, Subfamily D
-
ATP-Binding Cassette Transporters
-
Antioxidants
-
Biomarkers
-
Fatty Acids
-
Histone Deacetylase Inhibitors
-
Reactive Oxygen Species
-
Valproic Acid
-
Acetyltransferases
-
Fatty Acid Elongases