Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy

Fourcade, Stéphane; Ruiz, Montserrat; Guilera, Cristina; Hahnen, Eric; Brichta, Lars; Naudí i Farré, Alba; Portero Otín, Manuel; Dacremont, Georges; Cartier, Nathalie; Wanders, Ronald; Kemp, Stephan; Mandel, Jean Louis; Wirth, Brunhilde; Pamplona Gras, Reinald; Aubourg, Patrick; Pujol, Aurora

doi:https://doi.org/10.1093/hmg/ddq082

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Issue date

2010

Author

Fourcade, Stéphane

Ruiz, Montserrat

Guilera, Cristina

Hahnen, Eric

Brichta, Lars

Naudí i Farré, Alba

Portero Otín, Manuel

Dacremont, Georges

Cartier, Nathalie

Wanders, Ronald

Kemp, Stephan

Mandel, Jean Louis

Wirth, Brunhilde

Pamplona Gras, Reinald

Aubourg, Patrick

Pujol, Aurora

Suggested citation

Fourcade, Stéphane; Ruiz, Montserrat; Guilera, Cristina; Hahnen, Eric; Brichta, Lars; Naudí i Farré, Alba; ... Pujol, Aurora. (2010) . Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy. Human Molecular Genetics, 2010, vol. 19, núm. 10, p. 2005-2014. https://doi.org/10.1093/hmg/ddq082.

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.

URI

http://hdl.handle.net/10459.1/58675

DOI

https://doi.org/10.1093/hmg/ddq082

Is part of

Human Molecular Genetics, 2010, vol. 19, núm. 10, p. 2005-2014