TY - JOUR
T1 - Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy
AU - Fourcade, Stéphane
AU - Ruiz, Montserrat
AU - Guilera, Cristina
AU - Hahnen, Eric
AU - Brichta, Lars
AU - Naudi, Alba
AU - Portero-Otín, Manuel
AU - Dacremont, Georges
AU - Cartier, Nathalie
AU - Wanders, Ronald
AU - Kemp, Stephan
AU - Mandel, Jean Louis
AU - Wirth, Brunhilde
AU - Pamplona, Reinald
AU - Aubourg, Patrick
AU - Pujol, Aurora
PY - 2010
Y1 - 2010
N2 - 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
AB - 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
U2 - https://doi.org/10.1093/hmg/ddq082
DO - https://doi.org/10.1093/hmg/ddq082
M3 - Article
C2 - 20179078
SN - 0964-6906
VL - 19
SP - 2005
EP - 2014
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 10
ER -