Human Molecular Genetics Advance Access published online on March 14, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn085
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Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy
1 Centre de Genètica Mèdica i Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona and CIBERER, ISCIII, Spain 2 Institut de Neuropatologia de Bellvitge, Universitat de Barcelona, Spain 3 Departament de Medicina Experimental, Universitat de Lleida-IRBLLEIDA, Spain 4 Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands 5 Bioquimica i Biologia Molecular, and Institut de Biomedicina IBUB, Universitat de Barcelona and CIBER Fisiopatologia de la Obesidad y Nutrición, ISCIII, Spain 6 CIBERNED, ISCIII, Spain 7 Catalan Institution of Research and Advanced Studies (ICREA) Barcelona, Spain
* To whom correspondence should be addressed: CGMM, IDIBELL, Hospital Duran i Reynals, Gran Via s/n, km 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Spain. Tel: +34 932607343; Fax: +34 932607414; Email: apujol{at}idibell.org
Received January 17, 2008; Revised March 11, 2008; Accepted March 11, 2008
X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disorder, characterized by progressive cerebral demyelination (CCALD) or spinal cord neurodegeneration (adrenomyeloneuropathy, AMN), adrenal insufficiency and accumulation of very long-chain fatty acids (VLCFA) in tissues. The disease is caused by mutations in the ABCD1 gene, which encodes a peroxisomal transporter that plays a role in the import of VLCFA or VLCFA-CoA into peroxisomes. The Abcd1 knock-out mice develop a spinal cord disease that mimics AMN in adult patients, with late onset at 20 months of age. The mechanisms underlying cerebral demyelination or axonal degeneration in spinal cord are unknown. Here, we present evidence by GC/MS that MDAL (malonaldehyde-lysine), a consequence of lipoxidative damage to proteins, accumulates in the spinal cord of Abcd1 knockout mice as early as 3.5 months of age. At 12 months, Abcd1– mice accumulate additional proteins modified by oxidative damage arising from metal-catalyzed oxidation and glycoxidation/lipoxidation. While we show that VLCFA excess activate enzymatic antioxidant defences at the protein expression levels, both in neural tissue, in ex-vivo organotypic spinal cord slices from Abcd1– mice and in human ALD fibroblasts, we also demonstrate that the loss of Abcd1 gene function hampers oxidative stress homeostasis. We find that the 
-tocopherol analog Trolox is able to reverse oxidative lesions in vitro, thus providing therapeutic hope. These results pave the way for the identification of therapeutic targets that could reverse the deregulated response to oxidative stress in X-ALD.
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