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Human Molecular Genetics Advance Access originally published online on March 14, 2008
Human Molecular Genetics 2008 17(12):1762-1773; doi:10.1093/hmg/ddn085
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy

Stéphane Fourcade1,2,3, Jone López-Erauskin1,2,3, Jorge Galino1,2,3, Carine Duval1,2,3, Alba Naudi4, Mariona Jove4, Stephan Kemp5,6, Francesc Villarroya7,8, Isidre Ferrer3,9, Reinald Pamplona4, Manuel Portero-Otin4 and Aurora Pujol1,2,3,10,*

1 Centre de Genètica Mèdica i Molecular, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain 2 CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain 3 Institut de Neuropatologia de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain 4 Departament de Medicina Experimental, Universitat de Lleida-IRBLLEIDA, Lleida, Spain 5 Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry 6 Department of Pediatrics, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE, Amsterdam, The Netherlands 7 Bioquimica i Biologia Molecular and Institut de Biomedicina IBUB, Universitat de Barcelona, Barcelona, Spain 8 CIBER Fisiopatologia de la Obesidad y Nutrición, ISCIII, Barcelona, Spain 9 CIBER de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain 10 Catalan Institution of Research and Advanced Studies (ICREA) Barcelona, Spain

* To whom correspondence should be addressed at: 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; Accepted March 11, 2008

X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disorder, characterized by progressive cerebral demyelination cerebral childhood adrenoleukodystrophy (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 knockout 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 gas chromatography/mass spectrometry that 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 activates enzymatic antioxidant defenses 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 {alpha}-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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