期刊
HUMAN MOLECULAR GENETICS
卷 19, 期 10, 页码 2005-2014出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddq082
关键词
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资金
- European Commission [LSHM-CT2004-502987, FP7-241622]
- European Leukodystrophy Association (ELA) [2006-043I4, 2007-018F4]
- Spanish Institute for Health Carlos III [2007-018F4, FIS PI080991, FIS PI051118, 2006-031I4]
- Autonomous Government of Catalonia [2009SGR85, 2009SGR735]
- Spanish Ministry of Science and Innovation [AGL2006-12433, BFU2009-11879/BFI]
- Spanish Ministry of Health [RD06/0013/0012, PI081843]
- 'La Caixa' Foundation
- European Union
- ICREA Funding Source: Custom
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.
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