title: Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy.
abstract: 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.
authors.affiliation: Centre de Genètica Mèdica i Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fourcade
authors.forename: Jone
authors.initials: J
authors.lastname: López-Erauskin
authors.forename: Jorge
authors.initials: J
authors.lastname: Galino
authors.forename: Carine
authors.initials: C
authors.lastname: Duval
authors.forename: Alba
authors.initials: A
authors.lastname: Naudi
authors.forename: Mariona
authors.initials: M
authors.lastname: Jove
authors.forename: Stephan
authors.initials: S
authors.lastname: Kemp
authors.forename: Francesc
authors.initials: F
authors.lastname: Villarroya
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otin
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
mesh_terms: D000326:Adrenoleukodystrophy / Q000378:metabolism*; D000818:Animals; D002374:Catalase / Q000378:metabolism; D054422:Chemokine CCL22 / Q000235:genetics / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008239:Lysine / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D013116:Spinal Cord / Q000378:metabolism*; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2
chemical_list: D002374:Catalase; D054422:Chemokine CCL22; D002839:Chromans; D005227:Fatty Acids; D008239:Lysine; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C515483:Ccl22 protein, mouse; C017364:hexacosanoic acid; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid